Pharmacokinetics and bioavailability studies of generic ondansetron, and the innovator preparation, in healthy Thai male volunteers.

The pharmacokinetics and bioequivalence of two oral formulations of ondansetron were evaluated; Zetron (Biolab Pharmaceutical, Bangkok, Thailand), as the test formulation and Zofran (Glaxo Wellcome Operations, Greenford, UK), as the reference formulation. The two products were administered as a single oral dose of 8 mg according to a randomized two-way crossover design to 12 healthy Thai male volunteers. The washout period between treatment was 1 week. Ondansetron plasma concentrations were measured using HPLC. The oral bioavailability of ondansetron averaged 67 per cent and the elimination half-life after oral administration was 5.6 hours. The means and parametric 90 per cent CI of the ratios of Cmax and AUC 0-alpha [mu Zetron (Test)/mu Zofran (Reference)] were 0.95 (0.84-1.07) and 0.94 (0.80-1.10), respectively. These values were well within the bioequivalence range of 0.8-1.25 as established by the US-FDA. The mean difference of Tmax (Test-Reference) was approximately 20 per cent. Thus, our study demonstrated bioequivalence of the two products (Zetron and Zofran) regarding the rate and extent of absorption.

A nonprimate animal model applicable to zidovudine pharmacokinetics in humans: inhibition of glucuronidation and renal excretion of zidovudine by probenecid in rats.

The monkey is considered the best animal model to study the pharmacokinetics of zidovudine (azidothymidine, AZT) because humans and monkeys eliminate 60 to 75% of AZT by metabolism to the 5'-O-glucuronide (GAZT), in contrast to other experimental animals, which excrete most of the drug unchanged in the urine. It has become increasingly difficult and costly to use monkeys in research. Therefore, we undertook studies to determine the suitability of the rat as an alternative animal model to study the pharmacokinetics of AZT. In the initial experiments, [3H]AZT was administered i.v. at doses of 19, 60 and 187 mumol/kg to male Sprague-Dawley rats with intact bile ducts. The respective values (mean +/- S.D.) for total clearance of AZT were 2.4 +/- 0.2, 2.3 +/- 0.3 and 1.8 +/- 0.4 l/hr/kg and for renal clearance were 1.7 +/- 0.2, 1.8 +/- 0.4 and 1.5 +/- 0.4 l/hr/kg. The renal clearance of AZT was approximately equal to renal plasma flow of rats (1.5 l/hr/kg), suggesting that in addition to filtration, AZT is also efficiently secreted in the kidney of the rat. The respective values for volume of distribution at steady state were 1.3 +/- 0.2, 1.0 +/- 0.2 and 0.84 +/- 0.19 l/kg (P less than .05) and elimination half-life were (harmonic mean) 0.55, 0.44 and 0.46 hr. Urinary excretion of AZT as unchanged drug in intact rats accounted for 70 +/- 6, 79 +/- 6, and 83 +/- 12% of the dose, whereas only 0.7 to 0.8% of the dose was recovered in the urine as GAZT. Rats with exteriorized bile ducts, the proposed alternative animal model, were given an i.v. dose of 60 mumol/kg of [3H]AZT. To test the effect of a concurrently administered drug on the elimination of AZT in the model, some rats with bile duct cannulas were pretreated with probenecid, a known inhibitor of AZT elimination in humans. Urine and bile were collected to quantify the formation of GAZT. GAZT was identified by fast atom bombardment mass spectrometry as the major metabolite of AZT in the rat. GAZT excretion in the bile and urine accounted for 11 +/- 3% of the dose in saline-treated rats, compared to only 1.4 +/- 0.3% in rats treated with probenecid (P less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibition and induction of theophylline metabolism by 8-methoxypsoralen. In vivo study in rats and humans.

The effects of 8-methoxypsoralen (8-MOP) on the metabolism of theophylline were studied in rats and humans. Rats were randomized into three groups and prepared with iv jugular catheters. Group I (N = 4) received a single ip injection of 27 mg/kg of 8-MOP, group II (N = 5) vehicle (corn oil), and group III (N = 4) 50 mg/kg/day of 8-MOP for 3 days. Rats were subsequently administered 15 mg/kg of theophylline iv, and timed blood samples (0.2 ml) were assayed for theophylline by HPLC. Theophylline clearance (ml/min/kg; mean +/- SD) was 1.7 +/- 0.3, 2.4 +/- 0.5, and 9.5 +/- 1.6 in groups I, II, and III, respectively. The half-life (harmonic mean) from 0.5 to 12 hr was 7.2, 3.6, and 0.8 hr. Urinary excretion of unchanged theophylline (mean +/- SD) from 0 to 24 hr was 60 +/- 10, 41 +/- 6, and 13 +/- 3% of the administered dose. In a crossover study, three healthy, male, nonsmokers received 600 mg of oral theophylline. Urine and plasma were collected for 48 hr. One week later, subjects received 1.2 mg/kg of oral 8-MOP followed in 1 hr by 600 mg of oral theophylline. Mean residence time of theophylline increased from 10.7, 17.2, and 12.2 hr in the control period, to 20.3, 19.0, and 18.4 hr after 8-MOP. The AUC (microgram.hr/ml) of theophylline increased from 204, 213, and 204, to 555, 364, and 432, while clearance (ml/min/kg) decreased from 0.74, 0.57 and 0.63, to 0.27, 0.33, and 0.30, respectively. Urinary excretion of unchanged theophylline from 0 to 48 hr increased from 14, 14, and 15, to 24, 21, and 20%. We conclude that 8-MOP administered acutely is a potent inhibitor of theophylline metabolism and chronically in the rat is a powerful inducer.

Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans.

The acute effect of a single oral dose of methoxsalen on the pharmacokinetics of caffeine was investigated in five nonsmoking volunteers with psoriasis. Caffeine, 200 mg orally, was administered to each subject at baseline before treatment with methoxsalen. One week later each subject was given a single oral dose of 1.2 mg/kg methoxsalen 1 hour before administrations of another oral dose of 200 mg caffeine. The clearance of caffeine declined markedly from 110 +/- 17 ml/min (mean +/- SE) in the control study to 34 +/- 5 ml/min after methoxsalen. During the period of maximum inhibition the mean elimination half-life of caffeine increased from 5.6 hours at baseline to 57 hours after administration of methoxsalen. The peak concentration of caffeine and the time to reach the peak concentration of caffeine were not affected by pretreatment with methoxsalen. Thus, methoxsalen, administered acutely, is a potent inhibitor of caffeine metabolism in humans with psoriasis. Results of this investigation suggest that the elimination of concurrently administered drugs may be inhibited in patients receiving methoxsalen. In comparison with other drugs, methoxsalen is the most potent inhibitor of drug metabolism in humans. Other work has shown that inhibition of drug metabolism by methoxsalen is associated with both extensive covalent binding of metabolite(s) of methoxsalen to liver microsomal protein in vitro and in vivo and inactivation of cytochrome P-450.

Inhibition and induction of drug biotransformation in vivo by 8-methoxypsoralen: studies of caffeine, phenytoin and hexobarbital metabolism in the rat.

The effects of 8-methoxypsoralen (8-MOP) on drug metabolism in vivo were studied in catheterized rats. Rats were pretreated with a single i.p. injection of 5.4 or 27 mg/kg of 8-MOP, 30 min before an i.v. injection of either caffeine (CA; 10 mg/kg), hexobarbital (HB; 40 mg/kg), phenytoin (DPH; 15 mg/kg) or 5-(4'-hydroxyphenyl)-5-phenylhydantoin (HPPH; 15 mg/kg). Clearance of CA, HB and DPH, respectively (drugs eliminated primarily by phase-1 biotransformation), decreased from 0.25 +/- 0.02, 2.9 +/- 0.2 and 1.6 +/- 0.1 liters/kg/hr (means +/- S.E.) in control rats to 0.062 +/- 0.006, 0.65 +/- 0.15 and 0.09 +/- 0.03 liters/kg/hr in rats pretreated once with 27 mg/kg of 8-MOP. In contrast, the clearance of HPPH, which is eliminated primarily by glucuronidation, decreased only slightly from 1.3 +/- 0.1 liters/kg/hr in controls to 0.89 +/- 0.02 liters/kg/hr in rats pretreated with a single injection of 27 mg/kg of 8-MOP. Induction of drug metabolism by 8-MOP was studied in vivo in rats pretreated with 50 mg/kg/day of 8-MOP for 3 days and given an i.v. injection of CA, HB, DPH or HPPH 24 hr after their last pretreatment. This regimen increased the clearance of CA from 0.25 +/- 0.02 liters/kg/hr in controls to 1.08 +/- 0.04 liters/kg/hr in pretreated rats but had no significant effect on the elimination of HB, DPH and HPPH. Thus, acutely, 8-MOP is a potent, nonselective inhibitor of phase-1 metabolism in vivo. In contrast, chronically, it is a specific inducer of the metabolism of CA.(ABSTRACT TRUNCATED AT 250 WORDS)