Journal of Veterinary Pharmacology and Therapeutics, 1981
of theophylline in swine: a potential model for human drug b i o a d a b i l i t y studies. J. ve... more of theophylline in swine: a potential model for human drug b i o a d a b i l i t y studies. J. vet. Pharmacol. Therap. 4, 233-239. The pharmacokinetics of theophylline in swine were investigated following the oral and intravascular administration of single doses of theophylline free base. The mean half-life of theophylline following intravascular administration was 11.0 h, and the apparent specific volume of distribution was 0.61 liter/kg. Following oral administration, theophylline in solution was absorbed quite rapidly with a bioavailability of 79%. The similarity of the pharmacokinetics of theophylline in swine and humans suggests that swine may provide a useful model for the study of the bioequivalency of theophylline dosage forms intended for human use. The pharmacokinetic characteristics of theophylline also favor its consideration for usage as a therapeutic agent in swine.
Journal of Pharmacokinetics and Biopharmaceutics, 1982
Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the do... more Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the dose was excreted into urine as the acetyl metabolite with 4-6% excreted unchanged. Plasma and urine data were not consistent when a linear pharmacokinetic model was used to describe the data. Sulfadimethoxine has a high affinity for plasma protein, and the data were subsequently fitted to a nonlinear model, which included saturable protein binding. The choice of a nonlinear model was further supported by a minimum value for the Akaike information criteria. The protein binding constant obtained was 2.8 x 104 M-1 and the total protein binding site concentration in plasma was 4.6 • 10-4 m. Both values are comparable with in vitro data. This result suggests that the nonlinear model involving protein binding can be successfully applied to pharmacokinetic data. The apparent biological half-life of sulfadimethoxine (free and bound) in plasma was 14 hr; however, the half-life of elimination of free drug was 1.25 hr. Following oral administration, all of the dose was absorbed with an apparent absorption half-life of 2.9 hr.
Journal of Pharmacokinetics and Biopharmaceutics, 1975
A pharmacokinetic model was developed to describe the absorption, distribution, metabolism, and e... more A pharmacokinetic model was developed to describe the absorption, distribution, metabolism, and excretion of cephapirin and its major metabolite, desacetylcephapirin, following intravenous and intramuscular administration of cephapirin in healthy adult subjects. The model involved a twocompartment open model for cephapirin in plasma and extravascular tissues and included metabolism of cephapirin to desacetylcephapirin in both the plasma compartment and the kidney. Renal metabolism of cephapirin was followed by excretion of the desacetylcephapirin into the urine. Clearance calculations and digital computer simulation supported these features of the model.
Journal of Pharmacokinetics and Biopharmaceutics, 1986
Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to pl... more Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivo protein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100 mg/kg and caffeine 20 mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3-347 micrograms/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p less than 0.05) from 13.1 +/- 1.8 mg (mean +/- SD, 54.6% of total) to 15.3 +/- 1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC) was reduced from 612 to 516 micrograms hr/ml. Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUC values (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.
Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline... more Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline hydrochloride/kg im. The antimicrobial activity of the serum was determined periodically, and the resulting data were treated statistically to determine the sources of variation. Variance in serum levels of oxytetracycline activity was attributed to dose, time of bleeding, order of dosing, animal, and assay. The total variance component was proportionately greater for the 11-mg/kg dose than for the 4.4-mg/kg dose. Animal variance increased with the higher dose level of oxytetracycline. The influence of dose on serum level was tested by applying a t test to the mean serum levels and their standard deviations at each bleeding time. The 4.4- and 11-mg/kg serum levels were significantly different (p less than 0.01) at all bleeding times. The 4.4-mg/kg serum levels mutliplied by 2.5 were not significantly different (p less than 0.05) from the 11-mg/kg serum levels at all bleeding times.
Radioiodinated serum albumin has been used as a blood marker to define and quantitate physiologic... more Radioiodinated serum albumin has been used as a blood marker to define and quantitate physiological volumes for 12 organs and tissue types. The concentration of gallium-67 in "blood-free" tissues of rats was also determined at various times after intravenous administration. Tissues were divided into two kinetically distinguishable types based on reported nonuniform distribution of the blood marker and the gallium distribution observed in the present study. Gallium distribution into the liver and spleen was observed to be slow, with a discernable accumulation phase followed by monoexponential elimination. In contrast, gallium accumulation into the stomach, small and large intestines, heart, lung, skin/adipose tissue, and muscle was rapid and elimination was monophasic.
The plasma and urine data obtained following intravenous administration of sulfamethazine to catt... more The plasma and urine data obtained following intravenous administration of sulfamethazine to cattle were fit to a one-compartment pharmacokinetic model with a half-life of elimination of 9 hr and a volume of distribution of 0.35 liter/kg. Sulfamethazine was eliminated by excretion of unchanged sulfamethazine (18%) into urine and by formation of three metabolites subsequently excreted into urine. Sulfamethazine also was administered as a solution, a rapid-release bolus, and a sustained-release bolus. The change in the urinary metabolic pattern with different routes of administration suggested that first-pass metabolism was occurring during the absorption process. The absorption half-life was 6 hr. The absorption process for the two solid boluses kinetically appeared to include a dissolution step.
The fluorometric assay for verapamil in plasma is not useful after oral drug administration becau... more The fluorometric assay for verapamil in plasma is not useful after oral drug administration because of interference by inactive, but fluorescent, metabolites extracted along with the parent drug. A GLC method using a flame-ionization detector after silylation allows the separation of unchanged active verapamil from the metabolites and quantitation to a sensitivity of 0.025 microgram/ml. After a single oral dose of drug in dogs, up to 80% of "fluorescent verapamil" represented inactive metabolites.
Folic acid absorption from the lumen of the rat small intestine in situ obeyed Michaelis--Menten ... more Folic acid absorption from the lumen of the rat small intestine in situ obeyed Michaelis--Menten kinetics. The values of Vmax and Km for absorption were 4.63 x 10(-7) M/min and 1.21 x 10(-6) M, respectively. Folic acid and methotrexate were mutual competitive inhibitors of absorption. Their Ki values were 1.28 x 10(-6) and 1.9 x 10(-5) M, respectively.
The absorption of methotrexate from the lumen of the rat small intestine, in situ, was found to o... more The absorption of methotrexate from the lumen of the rat small intestine, in situ, was found to obey Michaelis-Menten kinetics. The values of Vmax and K , for the absorption process were 4.78 X Mlmin and 1.49 X Keyphrases 0 GI absorption-methotrexate from rat small intestine in situ Absorption, GI-methotrexate from rat small intestine in situ Methotrexate-GI absorption from rat small intestine in situ 0 Antineoplastic agents-methotrexate, GI absorption from rat small intestine in situ M, respectively.
The low aqueous solubility of acronine (approximately 2 mg/liter) has been overcome by identifica... more The low aqueous solubility of acronine (approximately 2 mg/liter) has been overcome by identification of quaternary prodrug salts exhibiting apparent molar solubilities two to five orders of magnitude greater than acronine. The synthesis and kinetics of hydrolysis of the various prodrug acetylacroninium salts were studied, and the half-life for hydrolysis under conditions approximating the in vivo situation was estimated to be about 5 min. Such rapid reversion, together with the greatly increased solubility, appears to qualify the prodrug for intravenous use.
Table 111-Effect of 4,4'-Diisothiocyano-2,2'di~lfonnte Stilbene (11) and Calcium Chloride (111) o... more Table 111-Effect of 4,4'-Diisothiocyano-2,2'di~lfonnte Stilbene (11) and Calcium Chloride (111) on tbe Enhancement of Plasma Cefoxitln Levels and on Cefoxitin Disappearance from the Rat Rectal In Situ Loop by a-Glycerophosphnte (I), Sodium Tripolyphosphate, and Sodium Phytate' Adjuvant Additive Concentration Concentration None None I(205 mM) None Tripolyphosphate None I I (1 mg/mL) 111 (l8OmM) (108 mM) I1 (I mg/mL) 111 (l8OmMb Phytate (53 mM) None 11 (1 mg/mL) 111 (180 mM) Percent Disappearance of Cefoxitin at 1.5 h 5.4 f 5.8 38.7 f 8.1 16.8 f 6.3b 25.2 f 5.3 18.5 f 4.2 2 1. 9 f 7.1 21.8 f 5.1 22.5 f 5.4 7.6 t 3.9b 7.8 f 3.2b <13b 119 f 28/, 5 2 f I I 9 9 f 18 61 f I I 66 f <I3 67 f 8 77 f 12 <13b 0 Micrememas contained 15 mg of cefoxitin/mL and had a dosage volume of 100 fiL/lOO g of rat body weight; n 2 3. b p < 0.001 uersus adjuvant without additive. difference in their ability to permeate the rat rectal tissue. In the present study, we found that the coadjuvants tripolyphosphate and phytate substantially enhanced the absorption of cefoxitin only after their own permeation of the membrane was apparently enhanced by I. Thus, we speculate that adjuvant permeation of the mucosal membrane may be mechanistically necessary before enhanced compound absorption acrass the rectal membrane can occur. In conclusion, the enhancing action of I on rectal cefoxitin absorption appears to depend on the affinity of I to the protein fraction in the mucosal membrane. The weak enhancing ability of the phosphate coadjuvants when administered with cefoxitin alone may involve chelating activity and possible damage to the rectal mucosa. However, the large increase in drug absorption after coadministration of I with either chelating agent, tripolyphosphate or phytate. is not just a consequence of the added effect of the enhancing action of 1 and chelation. These phosphate derivatives apparently have a strong adjuvant efficacy which can be realized only when their own permeation of the mucosal membrane is enhanced by adjuvants such as I. REFERENCES (I) K.
The pharmacokinetics of canrenone and &#39;total metabolites&#39; after base hydrolysis w... more The pharmacokinetics of canrenone and &#39;total metabolites&#39; after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and &#39;total metabolites&#39; were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2 alpha) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2 beta) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of &#39;total metabolites&#39; after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of &#39;total metabolites&#39; was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and &#39;total metabolites&#39; were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.
• A drug-drug interaction exists between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 ... more • A drug-drug interaction exists between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate), whereby gemfibrozil increases pioglitazone plasma exposure. Substantial interindividual variability exists in the pharmacokinetic magnitude of this drug-drug interaction. • CYP2C8 *3 is associated with increased metabolism and decreased plasma exposure of pioglitazone. • Polymorphisms in CYP metabolizing enzyme genes, namely CYP2C19 and CYP2D6, have been shown to influence the magnitude of inhibitory drug-drug interactions. However, the extent to which CYP2C8 polymorphisms (e.g. CYP2C8 *3) affect the interaction between gemfibrozil and pioglitazone is not known. WHAT THIS STUDY ADDS • The CYP2C8 *3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil and pioglitazone. CYP2C8 *3 carriers experienced a larger relative increase in pioglitazone plasma exposure following gemfibrozil administration than wild-type homozygotes. • Consideration should be given to the contribution of polymorphic CYP2C8 alleles to interindividual variability in the pharmacokinetic magnitude of CYP2C8-mediated drug-drug interactions. AIM The objective of this study was to determine the extent to which the CYP2C8 *3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8 *3 genotype (n = 15, CYP2C8 *1/*1; n = 15, CYP2C8 *3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS Gemfibrozil significantly increased mean pioglitazone AUC(0,•) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8-to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,•) was 29.7% lower (P = 0.01) in CYP2C8 *3 carriers compared with CYP2C8 *1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8 *3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,•) compared with a 3.3-fold mean increase in CYP2C8 *1 homozygotes (P = 0.02). CONCLUSION CYP2C8 *3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.
Computer Methods and Programs in Biomedicine, 1986
MULTI-FORTE is an expanded version of the MULTI non-linear fitting programs written by Yamaoka et... more MULTI-FORTE is an expanded version of the MULTI non-linear fitting programs written by Yamaoka et al. The functions of the three original programs (including Gauss-Newton and Simplex fitting algorithms) have been combined and translated into FORTRAN 77 on the Macintosh computer for both speed and convenience. Models can be described in integrated equation form or as a system of differential equations. Bayesian estimation is also available. Improved numerical integration routines have been added including methods suitable for systems of &#39;stiff&#39; differential equations (Fehlberg&#39;s 4/5 Runge-Kutta method and Gear&#39;s DIFSUB subroutine). MULTI-FORTE is a user-friendly program taking data from keyboard or disk file to produce output on screen, printer, or disk file in tables or printer-type plots.
Journal of Veterinary Pharmacology and Therapeutics, 1981
of theophylline in swine: a potential model for human drug b i o a d a b i l i t y studies. J. ve... more of theophylline in swine: a potential model for human drug b i o a d a b i l i t y studies. J. vet. Pharmacol. Therap. 4, 233-239. The pharmacokinetics of theophylline in swine were investigated following the oral and intravascular administration of single doses of theophylline free base. The mean half-life of theophylline following intravascular administration was 11.0 h, and the apparent specific volume of distribution was 0.61 liter/kg. Following oral administration, theophylline in solution was absorbed quite rapidly with a bioavailability of 79%. The similarity of the pharmacokinetics of theophylline in swine and humans suggests that swine may provide a useful model for the study of the bioequivalency of theophylline dosage forms intended for human use. The pharmacokinetic characteristics of theophylline also favor its consideration for usage as a therapeutic agent in swine.
Journal of Pharmacokinetics and Biopharmaceutics, 1982
Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the do... more Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the dose was excreted into urine as the acetyl metabolite with 4-6% excreted unchanged. Plasma and urine data were not consistent when a linear pharmacokinetic model was used to describe the data. Sulfadimethoxine has a high affinity for plasma protein, and the data were subsequently fitted to a nonlinear model, which included saturable protein binding. The choice of a nonlinear model was further supported by a minimum value for the Akaike information criteria. The protein binding constant obtained was 2.8 x 104 M-1 and the total protein binding site concentration in plasma was 4.6 • 10-4 m. Both values are comparable with in vitro data. This result suggests that the nonlinear model involving protein binding can be successfully applied to pharmacokinetic data. The apparent biological half-life of sulfadimethoxine (free and bound) in plasma was 14 hr; however, the half-life of elimination of free drug was 1.25 hr. Following oral administration, all of the dose was absorbed with an apparent absorption half-life of 2.9 hr.
Journal of Pharmacokinetics and Biopharmaceutics, 1975
A pharmacokinetic model was developed to describe the absorption, distribution, metabolism, and e... more A pharmacokinetic model was developed to describe the absorption, distribution, metabolism, and excretion of cephapirin and its major metabolite, desacetylcephapirin, following intravenous and intramuscular administration of cephapirin in healthy adult subjects. The model involved a twocompartment open model for cephapirin in plasma and extravascular tissues and included metabolism of cephapirin to desacetylcephapirin in both the plasma compartment and the kidney. Renal metabolism of cephapirin was followed by excretion of the desacetylcephapirin into the urine. Clearance calculations and digital computer simulation supported these features of the model.
Journal of Pharmacokinetics and Biopharmaceutics, 1986
Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to pl... more Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivo protein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100 mg/kg and caffeine 20 mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3-347 micrograms/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (p less than 0.05) from 13.1 +/- 1.8 mg (mean +/- SD, 54.6% of total) to 15.3 +/- 1.1 mg (63.8% of total) by caffeine coadministration. The terminal half-life of ceftriaxone in plasma was shortened from 59 to 47 min, and the area under the plasma drug concentration-time curve (AUC) was reduced from 612 to 516 micrograms hr/ml. Although the peak drug concentrations and the times of peak concentration of ceftriaxone in tissues were not altered by caffeine administration, the elimination of ceftriaxone was increased, as indicated by generally shorter half-lives (decreases ranged from 17.5% in liver to 34.2% in brain) and lower AUC values (from 9.0% in heart to 54.5% in brain). These results suggest that caffeine does not alter the protein binding of ceftriaxone, but enhances the elimination of ceftriaxone in the rat.
Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline... more Fifteen Aberdeen Angus steers, 295-364 kg, were dosed with either 4.4 or 11 mg of oxytetracycline hydrochloride/kg im. The antimicrobial activity of the serum was determined periodically, and the resulting data were treated statistically to determine the sources of variation. Variance in serum levels of oxytetracycline activity was attributed to dose, time of bleeding, order of dosing, animal, and assay. The total variance component was proportionately greater for the 11-mg/kg dose than for the 4.4-mg/kg dose. Animal variance increased with the higher dose level of oxytetracycline. The influence of dose on serum level was tested by applying a t test to the mean serum levels and their standard deviations at each bleeding time. The 4.4- and 11-mg/kg serum levels were significantly different (p less than 0.01) at all bleeding times. The 4.4-mg/kg serum levels mutliplied by 2.5 were not significantly different (p less than 0.05) from the 11-mg/kg serum levels at all bleeding times.
Radioiodinated serum albumin has been used as a blood marker to define and quantitate physiologic... more Radioiodinated serum albumin has been used as a blood marker to define and quantitate physiological volumes for 12 organs and tissue types. The concentration of gallium-67 in &quot;blood-free&quot; tissues of rats was also determined at various times after intravenous administration. Tissues were divided into two kinetically distinguishable types based on reported nonuniform distribution of the blood marker and the gallium distribution observed in the present study. Gallium distribution into the liver and spleen was observed to be slow, with a discernable accumulation phase followed by monoexponential elimination. In contrast, gallium accumulation into the stomach, small and large intestines, heart, lung, skin/adipose tissue, and muscle was rapid and elimination was monophasic.
The plasma and urine data obtained following intravenous administration of sulfamethazine to catt... more The plasma and urine data obtained following intravenous administration of sulfamethazine to cattle were fit to a one-compartment pharmacokinetic model with a half-life of elimination of 9 hr and a volume of distribution of 0.35 liter/kg. Sulfamethazine was eliminated by excretion of unchanged sulfamethazine (18%) into urine and by formation of three metabolites subsequently excreted into urine. Sulfamethazine also was administered as a solution, a rapid-release bolus, and a sustained-release bolus. The change in the urinary metabolic pattern with different routes of administration suggested that first-pass metabolism was occurring during the absorption process. The absorption half-life was 6 hr. The absorption process for the two solid boluses kinetically appeared to include a dissolution step.
The fluorometric assay for verapamil in plasma is not useful after oral drug administration becau... more The fluorometric assay for verapamil in plasma is not useful after oral drug administration because of interference by inactive, but fluorescent, metabolites extracted along with the parent drug. A GLC method using a flame-ionization detector after silylation allows the separation of unchanged active verapamil from the metabolites and quantitation to a sensitivity of 0.025 microgram/ml. After a single oral dose of drug in dogs, up to 80% of &amp;amp;quot;fluorescent verapamil&amp;amp;quot; represented inactive metabolites.
Folic acid absorption from the lumen of the rat small intestine in situ obeyed Michaelis--Menten ... more Folic acid absorption from the lumen of the rat small intestine in situ obeyed Michaelis--Menten kinetics. The values of Vmax and Km for absorption were 4.63 x 10(-7) M/min and 1.21 x 10(-6) M, respectively. Folic acid and methotrexate were mutual competitive inhibitors of absorption. Their Ki values were 1.28 x 10(-6) and 1.9 x 10(-5) M, respectively.
The absorption of methotrexate from the lumen of the rat small intestine, in situ, was found to o... more The absorption of methotrexate from the lumen of the rat small intestine, in situ, was found to obey Michaelis-Menten kinetics. The values of Vmax and K , for the absorption process were 4.78 X Mlmin and 1.49 X Keyphrases 0 GI absorption-methotrexate from rat small intestine in situ Absorption, GI-methotrexate from rat small intestine in situ Methotrexate-GI absorption from rat small intestine in situ 0 Antineoplastic agents-methotrexate, GI absorption from rat small intestine in situ M, respectively.
The low aqueous solubility of acronine (approximately 2 mg/liter) has been overcome by identifica... more The low aqueous solubility of acronine (approximately 2 mg/liter) has been overcome by identification of quaternary prodrug salts exhibiting apparent molar solubilities two to five orders of magnitude greater than acronine. The synthesis and kinetics of hydrolysis of the various prodrug acetylacroninium salts were studied, and the half-life for hydrolysis under conditions approximating the in vivo situation was estimated to be about 5 min. Such rapid reversion, together with the greatly increased solubility, appears to qualify the prodrug for intravenous use.
Table 111-Effect of 4,4'-Diisothiocyano-2,2'di~lfonnte Stilbene (11) and Calcium Chloride (111) o... more Table 111-Effect of 4,4'-Diisothiocyano-2,2'di~lfonnte Stilbene (11) and Calcium Chloride (111) on tbe Enhancement of Plasma Cefoxitln Levels and on Cefoxitin Disappearance from the Rat Rectal In Situ Loop by a-Glycerophosphnte (I), Sodium Tripolyphosphate, and Sodium Phytate' Adjuvant Additive Concentration Concentration None None I(205 mM) None Tripolyphosphate None I I (1 mg/mL) 111 (l8OmM) (108 mM) I1 (I mg/mL) 111 (l8OmMb Phytate (53 mM) None 11 (1 mg/mL) 111 (180 mM) Percent Disappearance of Cefoxitin at 1.5 h 5.4 f 5.8 38.7 f 8.1 16.8 f 6.3b 25.2 f 5.3 18.5 f 4.2 2 1. 9 f 7.1 21.8 f 5.1 22.5 f 5.4 7.6 t 3.9b 7.8 f 3.2b <13b 119 f 28/, 5 2 f I I 9 9 f 18 61 f I I 66 f <I3 67 f 8 77 f 12 <13b 0 Micrememas contained 15 mg of cefoxitin/mL and had a dosage volume of 100 fiL/lOO g of rat body weight; n 2 3. b p < 0.001 uersus adjuvant without additive. difference in their ability to permeate the rat rectal tissue. In the present study, we found that the coadjuvants tripolyphosphate and phytate substantially enhanced the absorption of cefoxitin only after their own permeation of the membrane was apparently enhanced by I. Thus, we speculate that adjuvant permeation of the mucosal membrane may be mechanistically necessary before enhanced compound absorption acrass the rectal membrane can occur. In conclusion, the enhancing action of I on rectal cefoxitin absorption appears to depend on the affinity of I to the protein fraction in the mucosal membrane. The weak enhancing ability of the phosphate coadjuvants when administered with cefoxitin alone may involve chelating activity and possible damage to the rectal mucosa. However, the large increase in drug absorption after coadministration of I with either chelating agent, tripolyphosphate or phytate. is not just a consequence of the added effect of the enhancing action of 1 and chelation. These phosphate derivatives apparently have a strong adjuvant efficacy which can be realized only when their own permeation of the mucosal membrane is enhanced by adjuvants such as I. REFERENCES (I) K.
The pharmacokinetics of canrenone and &#39;total metabolites&#39; after base hydrolysis w... more The pharmacokinetics of canrenone and &#39;total metabolites&#39; after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and &#39;total metabolites&#39; were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2 alpha) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2 beta) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of &#39;total metabolites&#39; after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of &#39;total metabolites&#39; was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and &#39;total metabolites&#39; were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.
• A drug-drug interaction exists between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 ... more • A drug-drug interaction exists between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate), whereby gemfibrozil increases pioglitazone plasma exposure. Substantial interindividual variability exists in the pharmacokinetic magnitude of this drug-drug interaction. • CYP2C8 *3 is associated with increased metabolism and decreased plasma exposure of pioglitazone. • Polymorphisms in CYP metabolizing enzyme genes, namely CYP2C19 and CYP2D6, have been shown to influence the magnitude of inhibitory drug-drug interactions. However, the extent to which CYP2C8 polymorphisms (e.g. CYP2C8 *3) affect the interaction between gemfibrozil and pioglitazone is not known. WHAT THIS STUDY ADDS • The CYP2C8 *3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil and pioglitazone. CYP2C8 *3 carriers experienced a larger relative increase in pioglitazone plasma exposure following gemfibrozil administration than wild-type homozygotes. • Consideration should be given to the contribution of polymorphic CYP2C8 alleles to interindividual variability in the pharmacokinetic magnitude of CYP2C8-mediated drug-drug interactions. AIM The objective of this study was to determine the extent to which the CYP2C8 *3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8 *3 genotype (n = 15, CYP2C8 *1/*1; n = 15, CYP2C8 *3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS Gemfibrozil significantly increased mean pioglitazone AUC(0,•) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8-to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,•) was 29.7% lower (P = 0.01) in CYP2C8 *3 carriers compared with CYP2C8 *1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8 *3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,•) compared with a 3.3-fold mean increase in CYP2C8 *1 homozygotes (P = 0.02). CONCLUSION CYP2C8 *3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.
Computer Methods and Programs in Biomedicine, 1986
MULTI-FORTE is an expanded version of the MULTI non-linear fitting programs written by Yamaoka et... more MULTI-FORTE is an expanded version of the MULTI non-linear fitting programs written by Yamaoka et al. The functions of the three original programs (including Gauss-Newton and Simplex fitting algorithms) have been combined and translated into FORTRAN 77 on the Macintosh computer for both speed and convenience. Models can be described in integrated equation form or as a system of differential equations. Bayesian estimation is also available. Improved numerical integration routines have been added including methods suitable for systems of &#39;stiff&#39; differential equations (Fehlberg&#39;s 4/5 Runge-Kutta method and Gear&#39;s DIFSUB subroutine). MULTI-FORTE is a user-friendly program taking data from keyboard or disk file to produce output on screen, printer, or disk file in tables or printer-type plots.
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