Biochemical Pharmacology 178 (2020) 114045

Contents lists available at ScienceDirect

Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm

Review

Circadian rhythm in pharmacokinetics and its relevance to chronotherapy T

a,1 b,1 c c c,d,⁎
Dong Dong , Deguang Yang , Luomin Lin , Shuai Wang , Baojian Wu
a
School of Medicine, Jinan University, 601 Huangpu Avenue West, Guangzhou, China
b
Department of Cardiology, the First Affiliated Hospital of Jinan University, Guangzhou, China
c
Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China
d
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College
of Pharmacy, Jinan University, Guangzhou, China

A R T I C LE I N FO A B S T R A C T

Keywords: Dosing time accounts for a large variability in efficacy and/or toxicity for many drugs. Therefore, chronotherapy
Circadian rhythm has been shown to effectively improve drug efficacy and to reduce drug toxicity. Circadian changes in phar-
Chronopharmacokinetics macokinetics and pharmacodynamics (drug target) are two essential sources of time-varying drug effects.
Chronotherapy Pharmacokinetics determines the drug and metabolite concentrations (exposure) in target tissues/organs,
Circadian clock
thereby impacting drug efficacy and toxicity. Pharmacokinetic processes are generally divided into drug ab-
ADME
sorption, distribution, metabolism and excretion (so-called “ADME”). Recent years of studies have revealed
circadian (~24 h) rhythms in ADME processes, and clarified the underlying mechanisms related to circadian
clock regulation. Furthermore, there is accumulating evidence that circadian pharmacokinetics can be translated
to chronotoxicity and chronoefficacy. In this article, we review circadian rhythms in pharmacokinetic behaviors
along with the underlying mechanisms. We also discuss the correlations of circadian pharmacokinetics with
chronotoxicity and chronoefficacy.

1. Introduction Circadian rhythms are thought to be regulated and maintained by

the circadian clock system. In mammals, the clock (pacemaker) located
All forms of life on Earth are dictated by the daily changes (e.g., the in the suprachiasmatic nuclei (SCN) of the hypothalamus is called
intensity of sunlight) in the environment caused by the planet’s rota- “central clock” or “maser clock”. Clocks are also present in other parts
tion. It is thus not surprising that many aspects of physiology and be- of the brain and in other tissues/organs, and are called “peripheral
haviors in mammals vary periodically according to the times of the day clocks” or “slave clocks”. The central clock synchronies the peripheral
(so-called “circadian rhythms”, “circadian” means “about a day”). clocks via pathways involving nervous and hormonal signals. Circadian
Strictly speaking, circadian rhythms are free-running or endogenous clock has been implicated in regulation of a vast array of diseases in-
rhythms in the absence of any entraining stimuli. The period of inherent cluding sleep disorder, metabolic syndromes, inflammatory and cardi-
circadian pacemaker is about 25 h in humans [1]. However, due to the ovascular diseases [5–8]. The 24 h rhythms in drug efficacy and toxicity
entrainment by environmental time cues (i.e., time givers or zeitgebers, are also regulated by the circadian clock as the core source of rhythms.
the most important one refers to the sunlight), the inherited pacemaker However, identifying the exact mechanisms underlying chronotoxicity
manifests itself in a 24 h rhythm (so-called “diurnal rhythm”) [1]. It has and chronoefficacy is not an easy task because of a number of potential
been recognized that the efficacy and toxicity of many drugs are sub- contributing factors such as the rhythms in molecular targets, disease
jected to circadian rhythms (i.e., dosing time-dependency) with a severity, and pharmacokinetics (including enzymes and transporters).
variability of up to ten-fold, although the underlying mechanisms are Pharmacokinetics determines the drug and metabolite concentra-
incompletely known [2,3]. This “intra-individual variability” should be tions (exposure) in target tissues/organs, thereby impacting drug effi-
taken into account in pharmacotherapy for more effective and safer cacy and toxicity. Pharmacokinetic processes are generally divided into
applications of drugs, particularly for the treatment of rhythmic dis- drug absorption, distribution, metabolism and excretion (so-called
eases (i.e., symptoms vary greatly with the daily time) such as asthma, “ADME”). Recent years of studies have revealed circadian (~24 h)
myocardial infarction, and arthritis [4]. rhythms in ADME processes. Also, there is accumulating evidence that

⁎
Corresponding author at: College of Pharmacy, Jinan University Guangzhou, 510632, China.
E-mail address: [email protected] (B. Wu).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.bcp.2020.114045
Received 9 April 2020; Accepted 19 May 2020
Available online 22 May 2020
0006-2952/ © 2020 Elsevier Inc. All rights reserved.
D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

circadian pharmacokinetics can be translated to chronotoxicity and expression (Fig. 1). Additionally, epigenetic mechanisms (e.g., acet-
chronoefficacy. In this article, we review circadian rhythms in phar- ylation, deacetylation, and miRNAs) play a role in regulating expression
macokinetic behaviors along with the underlying mechanisms. and functions of clock genes [16–18].
Correlations of circadian pharmacokinetics with chronotoxicity and Cyclic transcription via the three cis-elements E-box, D-box and
chronoefficacy are also discussed. RORE are the fundamental working mechanism for circadian clockwork
(Fig. 1). Bmal1 and Clock are E-box-acting proteins, Dbp and E4bp4 are
D-box-acting proteins, whereas Rev-erb and Ror are RORE-acting pro-
2. Circadian clock system teins. The diurnal patterns of these proteins (clock components) are
depicted in Fig. 2A. The patterns of Bmal1 and Clock (characterized by
Circadian rhythms are regulated and maintained by the circadian the peak time at the later light phase) can be directly transmitted to
clock system generally consisting of the input pathways that provide their target genes (Fig. 2A). Dbp and E4bp4 constitute a reciprocal
time cues (e.g., light, food and temperature), the central oscillator mechanism of transcriptional regulation in which Dbp-mediated acti-
(pacemaker), and the output (or effector) pathways that control the vation dominates in the daytime whereas E4bp4-mediated suppression
behavior, physiology and metabolism of the organisms. In mammals, dominates in the nighttime (Fig. 2A). Such mechanism generates a
the central pacemaker is located in the suprachiasmatic nuclei (SCN) of circadian rhythm in target gene whose pattern resembles that of Dbp
the hypothalamus. Light as the main input signal is perceived by the (peaking at the later light phase) (Fig. 2A). Likewise, Ror and Rev-erb
intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina play an antagonistic role in transcriptional regulation, and the diurnal
and transmitted to SCN via the retinohypothalamic tract (RHT) [9]. pattern of their target gene resembles that of Ror (or antiphase to that
Glutamate and PACAP (pituitary adenylate cyclase-activiting peptide) of Rev-erb, characterized by the trough time at the later light phase)
are two principal neurotransmitters in RHT, that mediate light effects (Fig. 2A).
on the clock genes (e.g., Per1,2) in SCN through phosphorylated CREB
(cyclic AMP responsive element-binding protein) [10]. ipRGCs serve
the SCN, but may not support the image-forming vision (that is medi- 3. Circadian rhythms in drug absorption
ated by the rods and cones). This is why some blind individuals
(probably due to the lack of rods and cones) can maintain circadian Time-varying absorption and pharmacokinetics in animals and hu-
entrainment (melatonin secretion is responsive to light exposure) [11]. mans have been documented for many drugs (e.g., indomethacin, cy-
The central clock generates oscillations in expression of genes (i.e., closporine, nifedipine, valproic acid, theophylline and digoxin) fol-
clock-controlled genes, CCGs) using a negative feedback mechanism lowing oral administration [19–24]. Despite the lack of sufficient
(so-called “transcriptional-translational feedback loop”) [12]. The po- experimental evidence, it is postulated that circadian changes in the
sitive regulators (BMAL1 and CLOCK or NPAS2) form a heterodimer to physiological factors such as gastric pH, gastric emptying time, gas-
activate the gene transcription of negative regulators (PER1,2 and trointestinal mobility and blood flow may contribute to the time-de-
CRY1,2) and other CCGs via direct binding to the E-box cis-element in pendent drug absorption [25].
the promoters (Fig. 1) [13]. Approximately 43% of all protein coding Recent years of studies have highlighted a critical role of intestinal
genes are CCGs [14]. It is noted that another PER homolog PER3 may transporters in circadian drug absorption (Table 1). There are two types
not have a role in regulating circadian rhythms, but contributes to sleep of drug transporters. Uptake transporters mediate cellular uptake of
homeostasis [15]. Following gene translation and protein accumula- drug molecules, and facilitate drug absorption across the enterocytes.
tion, PERs and CRYs in turn inhibit the activity of the positive reg- Efflux transporters or exporters mediate efflux transport (excretion) of
ulators, decreasing their own expression and expression of other CCGs drug molecules out of cells, precluding drug absorption. Expression of
(Fig. 1). Once proteins of negative regulators are degraded, their in- several uptake transporters (e.g., Slc15a1/PepT1 and Slc22a4/Octn1)
hibitory actions are no longer available. Positive regulators can bind to in small intestine oscillates with the times of the day [26–29]. Oscil-
target gene promoter to start a new cycle of transcription and transla- lations in the expression of Slc22a4 cause dosing time-dependent dif-
tion. The nuclear receptors RORα,β,γ and REV-REBα,β participate in ferences in the intestinal absorption of oral gabapentin (a Slc22a4
regulating the feedback loop. RORs activate while REV-ERBs inhibit substrate) [29]. Gabapentin absorption is significantly higher in the
transcription of Bmal1 and Cry1 (Fig. 1). Also, DBP and E4bp4 con- dark phase (ZT14) than in the light phase (ZT2) consistent with the
tribute to circadian robustness by synergistically regulating Per2 diurnal pattern of Slc22a4 protein [29]. Please note that ZT is zeitgeber

Fig. 1. Transcriptional-translational feed-

back loops of circadian clock. The positive
regulators (Bmal1 and Clock) form a het-
erodimer to activate the gene transcription
of negative regulators (Per1,2 and Cry1,2)
and other CCGs via direct binding to E-box
cis-element in the promoters. Following
gene translation and protein accumulation,
PERs and CRYs in turn inhibit the activity of
the positive regulators, decreasing their own
expression and expression of other CCGs.
Once proteins of negative regulators are
degraded, their inhibitory actions are no
longer available. Positive regulators can
bind to target gene promoter to start a new
cycle of transcription and translation. The
nuclear receptors Rors and Rev-rebs parti-
cipate in regulating the feedback loop. Rors
activate while Rev-erbs inhibit transcription
of Bmal1 and Cry1. Also, DBP and E4bp4
contribute to circadian robustness by sy-
nergistically regulating Per2 expression.

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D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

Fig. 2. (A) Circadian patterns for E-box, D-box, and RORE-driven expression. The patterns of Bmal1 and Clock (characterized by the peak time at the later light
phase) can be directly transmitted to their target genes. Dbp and E4bp4 constitute a reciprocal mechanism in transcriptional regulation in which Dbp activation
dominates in the daytime whereas E4bp4 suppression dominates in the nighttime. Such mechanism generate a circadian rhythm in target gene whose pattern
resembles that of Dbp (peaking at the later light phase). Likewise, Ror and Rev-erb play an antagonistic role in transcriptional regulation, and the diurnal pattern of
their target gene resembles that of Ror (or antiphase to that of Rev-erb, characterized by the trough time at the later light phase). (B) Diurnal intestinal expression of
mdr1a/Abcb1 and Abcc2 in mice. Time-varying intestinal absorption of Abcb1 substrates is negatively correlated with temporal expression of Abcb1, and a lower
drug absorption tends to occur at the onset of dark phase. Intestinal absorption of Abcc2 substrates tends to be higher when Abcc2 expression is low, and is lower
when Abcc2 expression is high. (C) A summary of drug-processing genes whose rhythms are driven by E-box, D-box, and/or RORE cis-element.

time in a 12 h light and 12 h dark cycle. ZT0 represents lights on and expression has been reported in the small intestine in mice and rats
ZT12 represents lights off. although circadian patterns may be strain- and sex-dependent
The mdr1a (also known as Abcb1a) gene and its protein product [26,37,38]. Oscillations in intestinal Abcc2 are associated with circa-
Abcb1 (an efflux transporter) are rhythmically expressed in the small dian changes in intestinal absorption of and systemic exposure of oral
intestine of mice and monkeys, peaking at the light–dark transition methotrexate (MTX, an Abcc2 substrate) [37]. MTX absorption tends to
[30–32]. Sex-specific circadian changes are found in Abcb1 mRNA and be higher when Abcc2 expression is low, and is lower when Abcc2
protein levels in ileum, circadian amplitudes being larger in female expression is high (Fig. 2B). Oscillating Abcc2 also contributes to in-
mice as compared to males [33]. Diurnal expression of Abcb1 has been testinal accumulation of irinotiecan, accounting for circadian changes
translated to circadian changes in intestinal absorption of and systemic in the irinotiecan toxicity [38]. Mechanistically, Abcc2 rhythm is ori-
exposure of drugs transported by Abcb1, for example, talinolol, lo- ginated from transcriptional regulation by Dbp and E4bp4 via the D-box
sartan, digoxin, oleandrin and talinolol [31,33–35]. Time-varying in- cis-element [37,39]. The rhythms of Dbp and E4bp4 can be traced back
testinal absorption of these Abcb1 substrates is negatively correlated to the central clock gene Bmal1 that directly drive rhythmic Dbp ex-
with temporal expression of Abcb1, and a lower drug absorption tends pression and indirectly regulates rhythmic E4bp4 via Rev-erbα as an
to occur at the onset of dark phase (Fig. 2B). The time-varying ab- intermediate [37].
sorption of the cardiac glycoside oleandrin (a main toxic ingredient of ABCG2 (BCRP) is another efflux transporter that plays a role in drug
Nerium oleander) may account for the dependence of oleander poisoning absorption. Intestinal Abcg2 displays circadian oscillations in mice
on the time of ingestion [36]. Circadian oscillation in mdr1a expression [40]. Circadian expression of Abcg2 is generated through transcrip-
is attributed to transcriptional regulation by Hlf and E4bp4, both are tional regulation by the clock component ATF4 (activating transcrip-
under the control of the central clock component Bmal1 [31,34]. tion factor 4) via a cAMP response element in the exon 1B promoter
Circadian time-dependency of Abcc2 (Mrp2, the second member of [40]. This temporal expression leads to circadian variation in intestinal
the C subfamily of the ATP-binding cassette efflux transporters) accumulation of and oral bioavailability of sulfasalazine, a typical

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D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

Table 1
Rhythmic enzymes and transporters involved in ADME processes.
Gene/Protein Expression level Location Peak timing Peak-to-valley ratio Model Ref

Pept1 mRNA Jejunum Light-to-dark transition 2.2 Rats [26]

Pept1 mRNA Small intestine Light-to-dark transition >3 Mice [27]
Pept1 Protein Small intestine Start of the dark phase >3 Mice [27]
Octn1 Protein Small intestine Start of the dark phase 2.0 Mice [29]
Octn1 Protein Small intestine Early dark phase >4 Mice [94]
mdr1a mRNA Ileum Light-to-dark transition >5 Mice [31]
Abcb1 Protein Ileum Light-to-dark transition ~3 Mice [31]
Abcb1 mRNA Small intestine Dark-to-light transition ~5 Monkeys [32]
Abcb1 mRNA Liver Dark-to-light transition ~5 Monkeys [32]
Abcc2 mRNA Jejunum Light-to-dark transition 2.5 Rats [26]
Abcc2 mRNA Small intestine Mid-light phase >2 Mice [37]
Abcc2 Protein Small intestine Mid-light phase >2 Mice [37]
Abcc2 mRNA Liver Light-to-dark transition ~3 Mice [70]
Abcc2 Protein Liver Light-to-dark transition ~1.5 Mice [70]
Abcg2 mRNA (exon 1B) Small intestine Mid-light phase >4 Mice [40]
Cyp1a1 mRNA Lung Early dark phase >3 Mice [61]
Cyp1a1 Protein Lung Mid-dark phase >3 Mice [61]
Cyp1a2 mRNA Liver Light-to-dark transition ~2 Mice [57]
Cyp1a2 Protein Liver Dark-to-light transition ~2 Mice [57]
Cyp2a4/5 mRNA Liver Light-to-dark transition >3 Mice [63]
Cyp2a4/5 Protein Liver Light-to-dark transition ~2 Mice [63]
Cyp2b10 mRNA Liver Mid-dark phase 2.8 Mice [56]
Cyp2b10 Protein Liver Dark-to-light transition ~2 Mice [63]
Cyp2c50 mRNA Liver Mid-dark phase ~3 Mice [55]
Cyp2e1 mRNA Liver Light-to-dark transition ~2 Mice [57]
Cyp2e1 Protein Liver Mid-dark phase ~2 Mice [57]
Cyp3a11 mRNA Small intestine Mid-light phase >2 Mice [67]
Cyp3a11 Protein Small intestine Early dark phase 1.5 Mice [67]
Cyp3a11 mRNA Liver Mid-light phase 1.8 Mice [67]
Cyp3a11 Protein Liver Mid-dark phase ~2 Mice [67]
Cyp4a10/14 mRNA Liver Dark-to-light transition >2 Mice [57]
Fmo5 mRNA Liver Light-to-dark transition ~3 Mice [69]
Fmo5 Protein Liver Light-to-dark transition ~2 Mice [69]
Sult1a1 mRNA Liver Early dark phase ~2 Mice [73]
Sult1a1 Protein Liver Mid-dark phase ~2 Mice [73]
Ugt1a1 mRNA Liver Light-to-dark transition >2 Mice [70]
Ugt1a1 Protein Liver Light-to-dark transition ~1.5 Mice [70]
Ugt2b1 mRNA Liver Late light phase ~1.5 Mice [71]
Ugt2b5 mRNA Liver Mid-light phase ~2 Mice [71]
Ugt2b35 mRNA Liver Mid-light phase ~2 Mice [71]
Ugt2b36 mRNA Liver Mid-light phase ~1.5 Mice [71]
Ugt2b37 mRNA Liver Mid-light phase >2 Mice [71]
Ugt2b38 mRNA Liver Mid-light phase >2 Mice [71]
Ugt2b Protein Liver Late dark phase ~1.7 Mice [71]
Oct2/Slc22a2 mRNA Kidney Mid-light phase >2 Mice [80]
Oct2/Slc22a2 Protein Kidney Mid-light phase >2 Mice [80]
Slc9a3 mRNA Kidney Mid-dark phase 2.5 Rats [123]
Slc9a3 mRNA Kidney Late light phase ~2 Mice [123]
Slc9a3 Protein Kidney Dark-to-light transition ~2 Mice [123]

Abcg2 substrate [40]. variations in the distribution of several drugs including lidocaine and
theophylline to erythrocytes [44–46]. The ratios of lidocaine con-
4. Circadian rhythms in drug distribution centration in erythrocytes to plasma are 0.74 and 0.48 when drug is
dosed at 22:00 PM and 10:00 AM, respectively [46]. However, no
To date, very few studies have been performed to investigate the temporal variation is found in the indomethacin concentration in ery-
circadian changes in drug distribution to tissues from systemic blood throcytes of elderly healthy individuals [47]. It is postulated that
circulation. Circadian oscillation in protein binding (fraction of un- temporal changes in erythrocytic penetration depend on the physico-
bound) is thought to be a factor contributing to dosing time-de- chemical properties of drugs as well as the plasma protein binding [47].
pendency of drug distribution [41,42]. For instance, fraction of un-
bound for diazepam is lower at 0.5 h after intravenous dosing in the 5. Circadian rhythms in drug metabolism
morning, and a negative correlation is observed between fraction of
unbound and total plasma level [43]. Thereby, diurnal alteration in Circadian variations in hepatic drug metabolism have been docu-
protein binding contributes to time-dependent changes in the rate of mented since 1967 [48]. Temporal variations in hepatic oxidation
diazepam distribution [43]. Free plasma levels of lidocaine show a 2- metabolism were first reported for p-nitroanisole in 1967, then for a
fold variation with respect to daily hours probably due to circadian batch of other compounds including aminopyrine, hexobarbital, ani-
time-dependent albumin (a major plasma protein) concentrations in line, benzphetamine, benzpyrene, biphenyl, imipramine and steroids in
plasma [41]. However, whether this temporal variation can be trans- the following years [48–51]. In particular, an inverse temporal corre-
lated to circadian changes in lidocaine distribution remains to be va- lation is established between the metabolic activity and drug effect
lidated. (reflected by sleeping time) for hexobarbital (a hypnotic drug) [50].
In the 1980s, Bruguerolle and coworkers reported time-dependent Temporal variations in hepatic glucuronidation and sulfation (for p-

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D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

nitrophenol and phenol) have been also recorded since 1985 [52]. by the circadian clock genes such as Bmal1, Rev-erbα/E4bp4 and Dbp
Temporal variations in conjugation reactions in the liver may explain [69].
more extensive metabolism of acetaminophen during the active phase Wang et al reported a diurnal rhythm in hepatic Ugt1a1 expression,
in both humans and rats [53,54]. Additionally, the level of reduced accounting for circadian detoxification of bilirubin and temporal var-
glutathione (a cofactor for glutathione conjugation) was shown to dis- iations in bilirubin level [70]. Bmal1 ablation abrogates the circadian
play circadian variations in the liver, that may contribute to chron- rhythms in Ugt1a1 expression and in bilirubin level in mice [70].
ohepatotoxicity of agents such as chloroform, styrene, and 1,1-di- Morphine shows dosing time-dependent glucuronidation and pharma-
chloroethylene [43]. All these early studies made significant cokinetics in mice [71,72]. Glucuronidation of morphine is more ex-
observations on circadian events in drug metabolism, although the tensive at the dosing time of ZT2 than at ZT14 owing to diurnal ex-
underlying mechanisms were unexplored. pression of Ugt2bs (enzymes responsible for morphine glucuronidation)
Rapid development of molecular biology techniques (e.g., molecule [72]. The circadian component Rev-erbα has been proposed as a cir-
cloning and gene editing) at the end of last century have facilitated cadian regulator of Ugt2bs [72]. Sult1a1 is rhythmically expressed in
investigations on drug metabolism at the molecular level. A number of mouse liver with higher levels in the nighttime [73]. Accordingly, he-
drug-metabolizing genes in mice have been identified as oscillating patic sulfation of p-nitrophenol and galangin (two Sult1a1 substrates)
genes at the mRNA, protein, and enzymatic activity levels, for example, are circadian time-dependent with a higher activity at ZT14 than at ZT2
Cyp1a2, Cyp2a4/5, Cyp2b10, Cyp2e1, Cyp3a11, Cyp4a10/14, Ces3, [73]. Mechanistically, Bmal1 generates and regulates circadian Sult1a1
Fmo5, Sult1a1, Ugt1a1, and Ugt2bs (Table 1) [55–57]. By using syn- expression through periodical binding to an E-box element and cyclic
chronized (serum shocked) cells, scientists have also established several transcriptional activation [73].
human CYP genes such as CYP2D6, CYP2E1, and CYP3A4 as potential It is becoming clear that molecular components of circadian clock
circadian genes, although further validation is needed in humans directly generate and regulate the diurnal rhythms of drug-metabo-
[58–60]. We will discuss the well-characterized diurnal drug-metabo- lizing genes via the E-box, D-box and/or RORE elements (Fig. 2C).
lizing enzymes, drugs with circadian metabolism, and the mechanisms Rhythmic expressions of Cyp2a4/5 and Fmo5 are driven by both D-box-
underlying the rhythmic expression in the following paragraphs. and D-box-acting proteins [62,63,69]. Ugt1a1 and Sult1a1 are E-box-
Cyp1a1 expression displays significant diurnal oscillation in mouse driven oscillating genes [70,73]. Cyp3a11 and two transporter genes
lung [61]. The Cyp1a1 rhythm is indirectly regulated by the Clock (Abcc2 and mdr1a) are D-box-driven oscillating genes [35,37,67,74].
protein through the transcriptional activator AhR [61]. Accordingly, Cyp2b10, Ces2, and Ugt2b are RORE-driven oscillating genes
benzo[α]pyrene, a ligand of AhR, induces the expression of Cyp1a1 in [63,75,72]. Despite the lack of in vivo validation, CYP3A4 rhythm is
mouse lung in an injection time-dependent manner [61]. Lavery and shown to be regulated by D-box-acting proteins [60].
coworkers report that Dbp regulates the circadian expression of Cyp2a4 Mounting evidence indicates an indirect mechanism for generating
and Cyp2a5 in mouse liver [62]. This is supported by the study of rhythmic expressions of drug-metabolizing genes by circadian clock.
Gachon et al in which the Cyp2a5 rhythm is blunted in Dbp/Tef/Hlf This mechanism involves cycling transcriptional factors (TFs)/nuclear
triple knockout mice [55]. Diurnal expression of Cyp2a4/5 results in receptors as the intermediates. The rhythms of clock output cycling TFs
dosing time-dependent metabolism of coumarin (ZT2 < ZT14) [63]. are propagated to their downstream target genes. Examples of such
The Clock protein is also reported to regulate diurnal expression of cycling TFs are AhR, Ppar-γ, Hnf4α, and Hnf1α [59,61,64,67]. They
Cyp2a4/5 and dosing time-dependency of coumarin metabolism [63]. contribute to rhythmic expression of Cyp1a1, Cyp2a5, Cyp3a11, and
Additionally, Deng et al identified Ppar-γ as a partial contributor to Cyp2e1, respectively [59,67,61,64]. It is noteworthy that the role of the
rhythmic expression of Cyp2a5 [64]. indirect mechanism in rhythm generation is secondary as compared to
Diurnal expression of Cyp2b10 leads to dosing time-dependent direct regulation mechanism by clock components because of moderate
metabolism (bioactivation) of cyclophosphamide (i.e., more extensive amplitude of cycling TFs (the peak-to-valley ratio is < 2).
metabolism at the dark-to-light transition and milder at the light-to- It is difficult to generalize quantitative rhythmic patterns (e.g.,
dark transition) in mice [63]. Gachon et al unraveled that the three PAR phase or peaking time) for drug-processing genes due to the complex
bZip proteins (Dbp, Hlf and Tef) regulate rhythmic expression of mechanisms as discussed above. This situation is further complicated by
Cyp2b10 through the constitutive androstane receptor [55]. However, an additional factor, namely, a potential delay in mRNA translation to
the Clock protein is also an important regulator of Cyp2b10 rhythm and protein product. For instance, translation of protein from mRNA is
of circadian cyclophosphamide metabolism [63]. Mechanistically, delayed ~8 h for Cyp2e1 and Cyp3a11, and ~4 h for Ppar-γ (Fig. 3A)
Clock protein represses Cyp2b10 transcription through Rev-erbα/β [57,67,64]. A large delay in mRNA translation is also observed for the
[57,63]. Hepatic Cyp2e1 expression oscillates with the times of the day clock genes such as Bmal1 and Clock [76]. However, qualitative mRNA
with higher levels in the dark phase [59]. This results in circadian time- patterns for diurnal drug-processing genes may be generalized ac-
dependent formation of the toxic metabolite N-acetyl-p-benzoquinone cording to the main circadian regulation mechanisms. E-box- and D-
imine from acetaminophen [65,66]. box-driven expressions tend to obey a pattern similar to that of Bmal1
Lin et al reported dosing time-dependent metabolism and systemic or Dbp protein (called “daytime type”, peaking time in the late light
exposure of both hypaconitine and triptolide (i.e., more extensive me- phase, e.g., Cyp2a4/5, Cyp3a11 and Fmo5) (Fig. 3B). RORE-driven ex-
tabolism and lower systemic exposure for ZT14 dosing as compared to pression follows a pattern antiphase to Rev-erbα (called “nighttime
ZT2 dosing) [67]. Circadian metabolism of these two compounds is type”, peaking time at the middle of dark phase, e.g., Cyp2b10)
attributed to diurnal expression of Cyp3a11, with a higher level at ZT14 (Fig. 3B). The mRNA patterns may be subjected to modifications by
than at ZT2 [67]. Likewise, diurnal expression of Cyp3a11 results in cycling TFs. For instance, Cyp2a5 mRNA is phase-shifted toward the
circadian variations in brucine metabolism and pharmacokinetics [68]. light–dark transition due to an additional action of Ppar-γ [64].
Brucine metabolism is more extensive (and systemic exposure is lower)
in the dark phase (ZT14 and ZT20) than in the light phase (ZT2 and 6. Circadian rhythms in drug excretion
ZT8) [68]. Mechanistic studies reveal that the core clock gene Bmal1
generates and regulates circadian Cyp3a11 expression through Dbp and Renal (or urinary) and biliary excretion constitute the main path-
Hnf4α [67]. Fmo5 expression displays a diurnal rhythm in mouse liver ways for drug excretion from the body. There are three processes in-
with peak levels at ZT10/14 and trough levels at ZT2/22 [69]. Ac- volved in renal excretion, namely, glomerular filtration, active tubular
cordingly, more extensive metabolism (Baeyer-Villiger oxidation) of secretion, and tubular reabsorption. A circadian rhythm has been de-
pentoxifylline is observed at dosing time of ZT14 than at ZT2 [69]. scribed in glomerular filtration rate (GFR) probably due to a temporal
Diurnal rhythm of Fmo5 is generated through transcriptional regulation variation in renal blood flow [77]. However, the effect of GFR rhythm

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D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

Fig. 3. (A) Schematic diagrams showing delay in translation of mRNA to protein for Cyp2e1/3a11 and Ppar-γ. (B) Typical diurnal mRNA patterns [daytime type (top)
and nighttime type (bottom)] for drug-processing genes according to the circadian regulation mechanisms. E-box- and D-box-driven expressions tend to obey a
pattern similar to that of Bmal1 or Dbp protein (peaking time in the late light phase, e.g., Cyp2a4/5, Cyp3a11 and Fmo5). RORE-driven expression follows a pattern
antiphase to Rev-erbα (peaking time at the first half of dark phase, e.g., Cyp2b10).

on circadian drug excretion is doubted because its amplitude is only diurnal expression of intestinal Abcb1 (Fig. 2B) in mice [35]. A tem-
about 10% of the mean [78]. White et al report a circadian rhythm in poral correlation is demonstrated between methotrexate (a che-
renal (and biliary) excretion of ampicillin with a 2-fold variability [79]. motherapeutic agent and Abcc2 substrate)-induced toxicity and in-
The authors propose that this rhythmicity is potentially accounted for testinal expression of Abcc2 (Fig. 2B) [37]. To be specific, AUC (area
by circadian changes in active tubular secretion mediated by anion under the curve) value and tissue accumulation of methotrexate are
carriers [79]. Circadian expression of OCT2 (organic cation transporter higher at dosing time of ZT14 than at ZT2 due to lower intestinal Abcc2
2) results in temporal changes in renal secretion of cisplatin (an an- expression at ZT14 than at ZT2 [37]. Accordingly, the hepatoxicity and
ticancer agent and OCT2 substrate), and therefore in dosing time-de- nephrotoxicity of methotrexate are dependent on circadian dosing time
pendent drug-induced nephrotoxicity [80]. Oscillation in OCT2 ex- (more severe toxicity at ZT14 than at ZT2) [37]. Oscillating Abcg2 in
pression is generated by circadian clock through the nuclear receptor the intestine has been identified as a key determinant to chron-
Ppar-γ (Table 1) [80]. Temporal variation has been also documented for opharmacokinetics of sulfasalazine although the toxicological con-
salicylate (a weak acid) whose excretion is influenced by urine pH [81]. sequence was not tested [40].
Salicylate excretion is more rapid (i.e., reabsorption is milder) in the There is accumulating evidence that CYP-mediated metabolism
daytime when urine pH is more alkaline, and is slower (i.e., reabsorp- plays an essential role in determining drug chronotoxicity. CYP-medi-
tion is stronger) in the nighttime when urine pH is more acid [81]. ated metabolism reactions can be either detoxification (the parent drug
Vonk et al reported a diurnal rhythm in biliary excretion of bro- is usually the toxic species in this case) or bioactivation (the metabolite
mosulphthalein in rats [82]. Excretion of bromosulphthalein into the is usually the toxic species in this case) pathways. Cyp2e1-mediated
bile is 25% higher in the middle of dark phase although the underlying formation of the toxic metabolite N-acetyl-p-benzoquinone imine
mechanism is unknown [82]. Biliary excretion of flomoxef (an ox- (NAPQI) is the main source of acetaminophen (APAP)-induced hepa-
acephem antibiotic) is greater in the early rest phase than in the early totoxicity. The hepatotoxicity of APAP displays a robust circadian
activity phase in both rats and humans [83,84]. Abcc2 protein is rhythm with more severe toxicity in the evening and milder toxicity in
rhythmically expressed in mouse liver with higher levels in the dark the morning in mice [65,66]. This chronotoxicity is attributed to
phase and lower levels in the light phase [85]. The diurnal pattern of diurnal hepatic expression of Cyp2e1 enzyme (high expression in the
Abcc2 in mouse liver differs from that in the intestine (Fig. 2B), sug- nighttime and low expression in the daytime, Fig. 4A). Mouse Cyp3a11
gesting tissue-specific differences in circadian gene expression. Diurnal is a rhythmic enzyme whose pattern is similar to that of Cyp2e1
hepatic expression of Abcc2 well explains why biliary excretion of (Fig. 4B). A batch of drugs (e.g., aconitine, hypaconitine, triptolide, and
phenolsulfonphthalein (an Abcc2 substrate) is more efficient in the dark brucine) detoxified by Cyp3a11 show circadian rhythmicity in toxicity
phase as compared to the light phase [85]. Per1 and Per2 double (more severe in the daytime) and the severity of toxicity is inversely
knockout mice show increased hepatic Abcc2 expression and abolished related to the protein level of Cyp3a11 [67,68,86] (Fig. 4B). Interest-
diurnal rhythm as well as enchased biliary excretion of phe- ingly, the chronotoxicity of aconitine and hypaconitine as the main
nolsulfonphthalein [85]. toxic ingredients may translate to the herb medicine Fuzi (lateral root of
Aconitum carmichaeli Debx) whose toxicity is more severe in the light
7. Pharmacokinetics-based chronotoxicity phase (ZT10) than in the dark phase (ZT22) [87].
Cyp2a4/5 participate in metabolism and detoxification of coumarin
Circadian expression of efflux transporters in the intestine can result in mice. Temporal variations in hepatic Cyp2a4/5 are contributing
in temporal variations in oral drug absorption, and therefore in dosing factors to the chronotoxicity of coumarin characterized by more severe
time-dependency of pharmacokinetics (systemic drug exposure). toxicity at the dark-to-light transition and miler toxicity at the light-to-
Accordingly, temporal oscillations in efflux transporters may be trans- dark transition (Fig. 4C) [63]. Multiple groups of investigators have
lated to drug chronotoxicity. For instance, chronotoxicity of oleandrin reported the chronotoxicity of the chemotherapeutic drug cyclopho-
(a cardio-toxin and Abcb1 substrate) is negatively associated with sphamide (CPA) in mice [63,88,89]. The toxicity of CPA is more severe

6
D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

Fig. 4. Correlations of diurnal Cyp2e1 (A) and Cyp3a11 (B) with drug chronotoxicity. APAP chronotoxicity is attributed to diurnal hepatic expression of Cyp2e1
(high expression in the nighttime and low expression in the daytime). A batch of drugs (e.g., aconitine, hypaconitine, triptolide, and brucine) detoxified by Cyp3a11
show circadian rhythmicity in toxicity (more severe in the daytime) and the severity of toxicity is inversely related to the level of Cyp3a11. Correlations of diurnal
Cyp2a4/5 (C) and Cyp2b10 (D) with drug chronotoxicity. Temporal variations in hepatic Cyp2a4/5 are contributing factors to the chronotoxicity of coumarin
characterized by more severe toxicity at the dark-to-light transition and miler toxicity at the light-to-dark transition. The toxicity of CPA is more severe at the dark-to-
light transition but miler at the light-to-dark transition. CPA is bioactivated to 4-OH-CPA (the active form) by Cyp2b10. Accordingly, circadian changes in CPA
toxicity parallels with those in hepatic Cyp2b10 expression.

at the dark-to-light transition but miler at the light-to-dark transition time in asthmatic children [95]. Theophylline dosed at 15:00 PM or
(Fig. 4D) [63,88]. CPA is bioactivated to 4-OH-CPA (the active form) by 21:00 PM shows superior pharmacokinetic properties (higher levels of
Cyp2b10 [63]. Accordingly, circadian change in CPA toxicity parallels Cmax, Tmax, and AUC) than drug dosed at 6:00 AM [95]. This help to
with that in hepatic Cyp2b10 expression (Fig. 4D) [63]. It is noteworthy explain why dosing at 15:00 PM or 21:00 PM results in the best effect
that in addition to temporal variation in Cyp2b10 metabolism, circa- on the airways [95]. Ohdo et al reported dosing time-dependent
dian rhythm in B cell survival is also a potential source of CPA chron- changes in the antiviral activity of IFNα in mice [96]. The authors
otoxicity [88] proposed that the rhythmicity in both pharmacokinetics and IFNα re-
The toxicity of irinotecan (CPT-11, a drug for treating colorectal ceptor function are the basis for the temporal changes in the pharma-
cancer) displays a circadian rhythm in mice [90]. CPT-11-induced cological effect [96].
toxicity (weight loss and leukopenia) is more severe in the late dark and Contributions of circadian pharmacokinetics to chron-
milder in the late light [90]. Circadian bioactivation (by Ces2) and opharmacological effects have been demonstrated for a group of an-
detoxification (by Ugt1a1) are identified as two critical determinants ticancer drugs (Table 2). For instance, the antitumor effect of erlotinib
for CPT-11 chronopharmacokinetics and chronotoxicity [90,91]. Cir- presents a diurnal rhythmicity. The growth of HCC827 xenograft in
cadian expression of Oct2 results in temporal changes in renal secretion mice is more potently inhibited by erlotinib in the early light phase
of cisplatin (an anticancer agent and Oct2 substrate) and in time-de- (ZT1) than in the early dark phase (ZT13) [97]. This is associated with a
pendency of renal drug accumulation [80]. Thereby, circadian oscilla- higher systemic exposure of erlotinib when drug is dosed at ZT1 as
tion in Oct2 leads to dosing time-dependent differences in cisplatin- compared to drug dosing at ZT13 [98]. Iurisci et al investigated the
induced nephrotoxicity [80,92]. To be specific, AUC value and Oct2- circadian efficacy of roscovitine using a Glasgow osteosarcoma xeno-
mediated renal uptake of cisplatin following intravenous injection at graft mouse model [99]. Roscovitine reduces the tumor growth by 35%
ZT14 (dark phase) are lower than those at ZT2 (light phase) due to a when administered in the active time of the mice (ZT19) and 55% when
higher rate of glomerular filtration at ZT14 than at ZT2 [80]. Accord- administered during their rest span (ZT3 or ZT11) [99]. This may be
ingly, the nephrotoxic effect of cisplatin is attenuated by injecting the attributed to the circadian changes in metabolism and pharmacoki-
drug at the times of day when renal expression of Oct2 is decreased netics of roscovitine [100]. Drug dosing at ZT3 generates higher sys-
[80]. Intriguingly, cisplatin-based chronotherapy has an advantage in temic and organ exposure due to a lower rate of metabolism as com-
relieving the side effects (e.g., neutropenia and nausea) of che- pared with ZT19 dosing [100].
motherapy for advanced non-small cell lung cancer patients [93]. Multiple clinical trials support the role of circadian pharmacoki-
netics in drug chronoefficacy. Because of daily variations in elimination
and pharmacokinetics, the plasma Ctrough values of sunitinib (a drug for
8. Pharmacokinetics-based chronoefficacy treatment of renal cell carcinoma, gastrointestinal stromal and pan-
creatic neuro-endocrine tumors) in patients are higher when adminis-
Circadian changes in pharmacokinetics can be also translated to tered in the afternoon or evening, and during these dosing times more
drug chronoefficacy. Nair and Casper first reported a temporal corre- stable drug concentrations are achieved than when administered in the
lation between the metabolism and the effect of a drug [50]. In their morning [101]. It is advised that sunitinib should be dosed in the
study, temporal variations in the sleeping time caused by hexobartital afternoon or evening for improved efficacy in clinical practice [101].
(a hypnotic drug) are negatively correlated with the circadian hex- Cmax and AUC0–8h of tamoxifen and endoxifen (the bioactive metabo-
obartital oxidase activity [50]. Dosing time-dependent differences in lite) are about 20% higher, and tamoxifen tmax is shorter (2.1 versus
the analgesic effect of pregabalin are attributable to circadian phar- 8.1 h) in humans after drug administration in the morning compared
macokinetics caused by oscillations in intestinal expression of Octn1 with evening dosing [102]. Dosing time-dependent endoxifen exposure
(organic cation transporter novel type 1) that mediates pregabalin up- may be partly accounted for by circadian CYP2D6 metabolism [102].
take into enterocytes and facilitates drug absorption [94]. The phar- However, whether the circadian variation in tamoxifen
macokinetics of theophylline varies greatly according to the dosing

7
D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

pharmacokinetics is relevant for drug efficacy remains to be validated

[99,100]
[97,98]

[124]

[125]
[102]
Ref
[102]. In addition, concentrations of rivaroxaban (an anticoagulant) are
higher at 12 h after evening drug intake than at 12 h after morning
intake (53.3 versus 23.3 ng/ml) in healthy individuals [103]. Rivar-

Least toxic time dependent on sex and strain: ZT7, ZT11 or ZT15
oxaban intake in the evening reduces morning concentrations of pro-
thrombin fragment 1 + 2 (a marker of thrombin generation) better at
8:00 AM than does drug administration on awakening, and this sup-
pression effect is longer lasting after evening intake [103].
Potential effects on clinical outcome or toxicity
9. Drug target-based chronoefficacy

Temporal variations in expression of drug targets are another main

Mean glycaemia drop: ZT1 > ZT13

source of drug chronoefficacy in addition to circadian pharmacoki-

Tumor inhibition: ZT1 > ZT13

Tumor inhibition: ZT3 > ZT19

Chronopharmacological effects

netics. In general, drug efficacy can be enhanced by administering

drugs at the time when the drug target is expressed the most. Circadian
clock direct or indirectly generates and regulates circadian rhythms in
molecular targets that are tightly associated with drug chronoefficacy
(Fig. 5 & Table 3). The antitumor effect of TNP-470 is more potent in
mice injected with drug in the early light phase than in animals injected
with drug in the early dark phase [104]. MetAP2 (methionine amino-
peptidase 2) is the drug target for TNP-470. The dosing time-dependent
antitumor effect of TNP-470 is closely related to the 24-h rhythm of
MetAP2 regulated by the transcription of circadian clock genes [105].
Rabbits
Model

Mice

Mice
Mice

Mice

The antitumor effect of the antiangiogenic agent SU1498 (a VEGFR-2

tyrosine kinase inhibitor) is enhanced when administered in early light
Circadian contributors: Ces2, Ugt1a1, abcb1a, abcb1b (liver and ileum), abcc2 (ileum)

phase compared with the early dark phase. This time-dependent change
Cmax and systemic exposure to sunitinib and SUI12662 (metabolite): ZT13 > ZT1

in antitumor efficacy is, at least in part, attributable to the circadian

variation in VEGF (vascular endothelial growth factor) production
regulated by the negative limbs of molecular clock [106]. The cytotoxic
effect of nutlin-3, a potent inhibitor of p53 (a tumor suppressor) de-
Potential circadian contributors: Cyp2d10, Cyp2d22, Cyp3a11 (liver)

gradation, on tumor cells varies according to the dosing time

Potential circadian contributors: Cyp3a11, Cyp3a13, Cyp1a2 (liver)

(ZT14 > ZT2) consistent with the circadian pattern of p53 protein
accumulation controlled by ATF4 through the ARF-MDM2 pathway
Potential circadian contributors: Cyp3a11, Cyp3a13 (liver)

[107]. Additional chemotherapeutic agents with chronoefficacy and

Systemic, kidney, adipose tissue exposure: ZT3 > ZT19

with circadian targets include IFN-β [108], everolimus [109], imatinib

[110], lapatinib [111], erlotinib [97], sulfasalazine [112], and N,N-
diethylaminobenzaldehyde [113] (Table 3).
Target-based chronoefficacy is also applicable to the drugs for
List of anticancer drugs with circadian pharmacokinetics and chronopharmacological effects.

Plasma and liver exposure: ZT18 > ZT6

treating many other types of diseases such as neuropathic pain,

Liver metabolic ratio: ZT19 > ZT3

thrombosis, metabolic disorders and colitis [114–120] (Table 3). Core

Systemic exposure: ZT1 > ZT13

clock proteins such as Rev-erbα/β, Rorα/γ, and Cry are ligand-re-

Circadian pharmacokinetics

sponsive (i.e., whose activity can be modulated by small-molecule li-

gands) [3]. Some of these proteins have been also shown to be involved
in disease pathogenesis, and therefore are potential drug targets and the
sources of drug chronoefficacy. For instance, Rev-erbα is implicated in
the regulation of colitis via the NF-κB/Nlrp3 axis, and activation of Rev-
erbα alleviates experimental colitis [8]. Zhou et al recently reported
that the anti-colitis efficacy of berberine (a Rev-erbα agonist) shows a
dosing time-dependency [119]. Dosing at ZT10 is associated with a
higher drug efficacy (a lower level of inflammation) as compared to
Roscovitine (seliciclib, cyclin-dependent kinase inhibitor)

dosing at ZT2 [119]. The berberine chronoefficacy is attributed to

diurnal expression of Rev-erbα as the drug target although the rhyth-
micity in colitis severity may also make a contribution [119]. Rev-erbα
is also involved in regulation of homocysteine homeostasis via mod-
ulation of catabolism and is proposed as a drug target for hyperho-
Irinotecan (topoisomerase I inhibitor)

mocysteinemia [121]. Circadian oscillation in Rev-erbα has been

Sunitinib (tyrosine kinase inhibitor)
Erlotinib (tyrosine kinase inhibitor)

translated to temporal variations in puerarin efficacy against hy-

perhomocysteinemia in mice, namely, a higher efficacy in the daytime
Tamoxifen (antiestrogenic)

(ZT10) and milder in the nighttime (ZT22) (Fig. 5) [120].

ZT, zeitgeber time.

10. Conclusion
Anticancer drug

Based on a survey of the literature, chronopharmacokinetics is lar-

gely attributed to circadian rhythms in the expression of drug-meta-
Table 2

bolizing enzymes and transporters that have an indispensable role in

ADME processes. Moreover, significant progress has been made

8
D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

Fig. 5. Circadian clock direct or indirectly generates

and regulates circadian rhythms in molecular targets
that are associated with drug chronoefficacy. As an
example, oscillations in Rev-erbα translate to tem-
poral variations in puerarin efficacy against hy-
perhomocysteinemia in mice [i.e., a higher efficacy
in the daytime (ZT10) and milder in the nighttime
(ZT22)] [120].

Table 3
Examples of drugs with chronoefficacy and circadian targets.
Drug Disease Circadian target Model Ref

TNP-470 Tumor MetAP2 Mice [104]

SU1498 Tumor VEGF Mice [106]
Nutlin-3 Tumor p53 protein Mice, UV.BAL-5.4G cells [107]
IFN-β Tumor IFN receptors Mice [108]
Everolimus Tumor mTOR protein Mice [109]
Imatinib Tumor PDGFR Mice [110]
Lapatinib Tumor EGFR Mice [111]
Erlotinib Tumor EGFR Mice [97]
Sulfasalazine Tumor xCT Mice [112]
N,N-diethylaminobenzaldehyde Tumor Aldh3a1 Mice [113]
Gabapentin Neuropathic pain α2δ-1 subunit Mice [114]
Rivaroxaban Thrombosis Activated factor X Rats [115]
RS102895 Atherosclerosis CCL2 Mice [116]
7-OH-DPAT Brain diseases DRD3 Mice [117]
Fluvoxamine Brain diseases 5-HTT Mice [118]
Berberine Chronic colitis Rev-erbα Mice [119]
Puerarin Hyperhomocysteinemia Rev-erbα Mice [120]

Abbreviations: Aldh3a1, aldehyde dehydrogenase 3a1; CCL2, chemokine (C–C motif) ligand 2; DRD3, dopamine D3 receptor; EGFR, epidermal growth factor receptor;
5-HTT, Serotonin (5-HT) transporter; PDGFR, platelet-derived growth factor receptor; 7-OH-DPAT, 7-hydroxy-N,N-dipropyl-2-aminotetralin.

regarding the regulatory mechanisms for circadian rhythms in drug- changes in drug pharmacokinetics in diurnal humans can be predicted
processing proteins. In general, rhythmic expression is driven by E-box, by using the data collected from nocturnal rodents. However, the basic
D-box or RORE-acting proteins that are molecular components of cir- mechanisms for circadian clock and for circadian gene expression are
cadian clock system. In addition, cycling transcription factors (nuclear well conserved in mammals [122]. Although the diurnal patterns of
receptors) regulated by circadian clock make a secondary contribution. mouse drug-processing genes cannot be directly mapped to those of
According to the main regulation mechanism, two rhythmic patterns of human counterparts, the regulatory mechanisms of these genes should
drug-processing genes at the mRNA level can be generalized qualita- be preserved between humans and rodents. On the other hand, current
tively in mice, namely, the daytime type (peaking in the late light data support that the circadian pharmacokinetics and mechanisms in
phase) and nighttime type (peaking in the mid-dark phase) (Fig. 3B). rodents may be extrapolated to humans. CYP3A4 is the human homo-
Circadian changes in the metabolism and pharmacokinetics can be logue of mouse Cyp3a11, and both are oscillating genes that driven by
translated to chronotoxicity or chronoefficacy for a plenty of drugs. D-box-acting clock components. Hepatic conjugation of acetaminophen
There is no general rule concerning the time-of-day for the highest or is more extensive during the active phase in both humans and rats.
lowest level of drug toxicity because it depends on multiple factors such Biliary excretion of flomoxef is greater in the early rest phase than in
as the toxic species of drug, diurnal rhythmicity in detoxifying enzymes the early activity phase in both humans and rats. It is envisioned that
and transporters. Concerns may be raised about whether the circadian the mechanism-based circadian pharmacokinetics would facilitate the

9
D. Dong, et al. Biochemical Pharmacology 178 (2020) 114045

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