Clopidogrel and drug metabolism: absence of effect on hepatic enzymes in healthy volunteers.

The influence of clopidogrel 75 mg, given once daily for 10 days on hepatic P-450 mixed function oxidases, was examined by assessing its effect on the disposition of antipyrine, on urinary 6-betahydroxycortisol (6beta-OHC) and on the plasma activity of gamma-glutamyl transpeptidase. This double-blind, randomized, placebo-controlled study was conducted in two parallel groups of 10 healthy young volunteers. Subjects were required to fast for 12 hours before and for 4 hours after dosing. Antipyrine 10 mg/kg was administered in the morning, two days before treatment (day -2) and 24 hours after the last dose of clopidogrel or placebo. Plasma levels of antipyrine, and urinary excretion of antipyrine, 3-hydroxymethyl-antipyrine and nor-antipyrine were measured over 36 hours post-drug for pharmacokinetic determinations. Bleeding time and platelet aggregation induced by 5 microM of ADP were measured before treatment (baseline) and at regular intervals after dosing during treatment. Clopidogrel treatment had a marked effect on platelet aggregation and bleeding time. No significant change in the disposition of antipyrine was observed after the ingestion of clopidogrel over 10 days: mean AUC ratio (+/-SEM) for plasma antipyrine was 1.021+/-0.023 for the clopidogrel group versus 1.001+/-0.019 for the placebo group; mean day 10/day -2 t 1/2 ratios were 1.019+/-0.018 and 1.027+/-0.023, respectively. Urinary excretions of antipyrine and metabolites were unchanged by clopidogrel compared to placebo. The changes in plasma cortisol concentrations, 6beta-OHC excretion and serum gamma-glutamyl transpeptidase activities observed at the end of treatment were fully comparable between the two treatment groups. Thus, the different tests showed no evidence of hepatic enzyme induction by clopidogrel in a pharmacologically effective dose regimen.

Similar bioavailability of single-dose oral and intravenous mesna in the blood and urine of healthy human subjects.

Although mesna has been used for more than a decade to reduce the incidence of hemorrhagic cystitis induced by ifosfamide and cyclophosphamide, the disposition of i.v. and oral mesna has not been adequately described. To obtain accurate bioavailability data for the design of mesna regimens, we developed procedures to preserve and measure mesna and dimesna in the blood and urine and studied 25 volunteer subjects who received single doses of i.v. mesna and four different formulations of oral mesna in a five-way randomized crossover study. The dose-adjusted area under the blood concentration-time curve showed no difference in bioavailability for i.v. and oral mesna; however, the maximum mesna concentration after oral doses was 16% of that estimated for i.v. doses. The short initial half-life of i.v. mesna indicated that mesna was rapidly cleared; however, the blood concentrations of mesna uniformly exceeded those of dimesna after oral as well as i.v. doses, which suggested that reduced mesna and oxidized mesna disulfide are in equilibrium. The ratio of mesna:dimesna was higher in protein-free plasma than it was in the urine, which suggested that most urinary mesna is produced by glomerular filtration of mesna rather than by renal tubular reduction of dimesna. The sum of mesna and dimesna excretion after the i.v. doses (73% of the dose) and the four oral formulations (68-73%) showed no difference in urinary bioavailability, consistent with the blood data. However, the urinary bioavailability of the therapeutically active free-thiol mesna was greater after i.v. doses (40% of the dose) than it was after oral doses (31-33%). The ratio of oral:i.v. mesna excretion ranged from 0.52-1.23 (mean, 0.82) among the 24 subjects. Urinary mesna concentrations exceeded 50 microM in all subjects for up to 12 h after oral doses as compared to 4 h after i.v. doses. About 90% of this mesna was excreted by hour 2 after i.v. doses and by hour 9 after oral doses. The mean maximum concentration of mesna in blood and excretion into urine were both 2.6 h after dosing. The oral formulations thus showed sustained urinary excretion, and their urinary bioavailability approached that of i.v. mesna.

Criteria to assess in vivo performance and bioequivalence of generic controlled-release formulations of carbamazepine.

PURPOSE: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled-release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time-concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), t(apical), and C(apical) (the arithmetic mean of the POT times and concentrations within 25% of Cmax, respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve. METHODS: These proposed parameters were used in two recent (single and multiple dose) two-way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. RESULTS: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time-concentration curves as assessed by visual inspection and the proposed parameters. CONCLUSIONS: The additional parameters examined may supplement the traditional single-point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption-rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Use of cytochrome-P450 mono-oxygenase 2 E1 isozyme inhibitors to delay seizures caused by central nervous system oxygen toxicity.

BACKGROUND: The neuronal origins and mechanisms of central nervous system oxygen toxicity are only partly understood. Oxygen free radicals are felt to play a major role in the production of CNS oxygen toxicity because of the interactions of free radicals with plasma membranes producing lipid peroxidation. The cytochrome P-450 monooxygenase system IIE1 isozyme is important in the brain. This led to trials of P450 monooxygense inhibitors for prevention of oxygen toxicity. Diethyldithiocarbonate (DDC) proved to be the most promising agent in this class; 21-aminosteroid lazeroid compounds have been successful in experimentally limiting pulmonary oxygen toxicity. This led to our trying to prevent neuronal oxygen toxicity by the use of 21-aminosteroid and six other drugs during hyperoxia. METHODS: In our experiments, mice were placed in an oxygen-filled hyperbaric chamber in paired experiments. One pre-treated mouse and one control mouse were exposed simultaneously to assess the efficacy of drugs in preventing seizures caused by hyperbaric oxygen at 5.1 atmospheres absolute. Time to seizure was observed through a port hole in the hull of the hyperbaric chamber. RESULTS: DDC, 21-aminosteroid and propranolol produced significant delays in the onset of seizures (p < 0.001) with no observable side effects; 1-aminobenzotriazole and disulfiram produced much shorter delays in the onset of seizures caused by hyperbaric oxygen and also had unacceptable side effects.

The action of 10 mg famotidine versus 200 mg cimetidine: onset and magnitude of antisecretory action within the first 2 hours after administration.

The introduction of over-the-counter histamine2 -receptor antagonists (H2 -RAs) makes it important to characterize these agents in terms of their different times to onset of action and magnitude of effect. The time to onset of action and the degree of gastric acid inhibition of the H2 -RAs famotidine and cimetidine at dosage levels approved for over-the-counter use (10 mg famotidine and 200 mg cimetidine) were compared. Twenty-four subjects with a history of heartburn of at least 2 months duration received 10 mg famotidine, 200 mg cimetidine, or placebo in a randomly assigned sequence of three treatment periods. Each period began with an overnight fast, followed by insertion of an intragastric pH probe during a 1-hour baseline monitoring phase, and, 1 hour later, administration of the test medications and monitoring of intragastric pH for an additional 2-hour period. The onset of acid inhibition occurred approximately 35 minutes after administration of either famotidine or cimetidine. Famotidine provided a significantly greater degree of efficacy on all three parameters monitored: percentage of time that gastric pH values were greater than 3.0, mean area-under-the-pH-curve-versus-time curve, and median pH (obtained at 5-minute intervals). Clearly, the over-the-counter dosage of famotidine (10 mg) provided gastric pH elevations that were as rapid and of superior degree than those induced by cimetidine 200 mg.

Physiologically based pharmacokinetics and the dermal absorption of 2-butoxyethanol vapor by humans.

It has generally been assumed that the skin contributes only minor amounts to the total uptake of solvent vapors, relative to the respiratory tract. Contrary to this assumption, the widely used glycol ether solvent, 2-butoxyethanol (BE), has been reported to be more effectively absorbed through the skin (75% of the total uptake) than through the lungs of humans (Johanson and Boman, 1991, Br. J. Ind. Med. 48, 788). The possibility that the finger prick blood sampling technique used in the Johanson and Boman study was confounded by locally high concentrations of BE at the site of absorption was suggested using a previously developed PBPK model (Corley et al., 1994, Toxicol. Appl. Pharmacol. 129, 61). The current study was conducted to verify the PBPK analysis and to determine whether or not the skin was the major site for absorption of BE vapor by exposing one arm from each of six human volunteers to 50 ppm 13C2-BE vapor for 2 hr. To evaluate the potential consequences of blood sampling techniques, samples were taken from both the unexposed arm (catheter; during and after exposure) and the exposed arm (finger prick; end of the exposure only) for analysis of both BE and its major metabolite, butoxyacetic acid (BAA). Butoxyacetic acid is responsible for the hemolysis observed in toxicity studies with laboratory animals. Humans, however, are significantly less sensitive to this effect. The concentration of BE in the finger prick blood samples averaged 1500 times higher than the corresponding concentration in venous blood sampled from a catheter installed in the unexposed arm at the end of the exposure. Blood BAA levels were generally within a factor of 4 of each other for the two techniques and, therefore, was considered a better indicator of systemic absorption. Urine was collected for 24 hr and analyzed for the following metabolites found in rat metabolism studies: free and conjugated BE, BAA, ethylene glycol (EG), and glycolic acid (GA), with only BAA detected in the human urine. More importantly, urinary BAA was found to be extensively conjugated ( approximately 67%) with glutamine, confirming recent reports. These results, coupled with PBPK modeling of worst-case exposure scenarios (no clothing, 100% of the body was exposed), demonstrated that no more than 15-27% (low-to-high relative temperatures and humidities), not 75%, of the total uptake of BE could be attributed to the skin of humans during simulated 8-hr exposures to the ACGIH TLV concentration of 25 ppm. Even less of the total uptake was attributed to the skin during simulations of exercise with whole-body exposures (5-9%) or by more realistic exposures of only the arms and head (1-8%). As a result, humans are unlikely to reach hemolytic concentrations of the metabolite BAA in blood following vapor exposures to BE.

Plasma levels of nicotine and safety of smokers wearing transdermal delivery systems during multiple simultaneous intake of nicotine and during exercise.

Although transdermal nicotine patches have been studied extensively under recommended conditions, the present studies were designed to assess the nicotine plasma levels and the safety of transdermal nicotine patches in smokers undergoing situations suspected to result in increased nicotine plasma levels. The first study examined the effects of increasing nicotine intake through sequential administration of a nicotine patch (day 2), a patch followed by consumption of nicotine gum (day 3), and a patch followed by gum consumption and cigarette smoking (day 4). In this study, nicotine plasma levels increased transiently after the addition of each nicotine source. Mean areas under the concentration-time curves from 0 to 24 hours (AUC0-24) for nicotine were 453 +/- 120 ng.hr/mL (day 2), 489 +/- 143 ng.hr/mL (day 3), and 485 +/- 143 ng.hr/mL (day 4). The second study evaluated the effects of physical exercise on the kinetics and the safety of two different types of nicotine transdermal devices: Nicoderm and Habitrol. The mean delivered dose of nicotine was higher with Nicoderm compared with Habitrol, and the two products were not considered to be bioequivalent. During a 20-minute exercise period, nicotine plasma levels increased by 13 +/- 9% for Nicoderm and 30 +/- 20% for Habitrol. This increase in nicotine plasma levels was probably related to the exercise-induced increase in peripheral circulation at the patch site. Results from both studies indicate a clinically nonsignificant increase in blood pressure and heart rate after the administration of nicotine. After exercise, subjects taking Habitrol tended to have a higher incidence of adverse events compared with baseline values. Safety profiles remained acceptable in both studies despite the increases in nicotine plasma levels. It was concluded that both superimposed nicotine sources and physical exertion result in short-lived plasma nicotine elevations and temporarily increase nicotine pharmacodynamic parameters without increased risk to the volunteers.

Steady state pharmacokinetics of hydrolysed bopindolol in young and elderly men.

Steady-state pharmacokinetic parameters of the new, long-acting beta-adrenoceptor blocker bopindolol have been measured in 17 young and 20 elderly healthy men. The t 1/2 beta and the AUC(0----24 h) of hydrolysed bopindolol (the active metabolite) were both increased (40% and 26%, respectively) in the elderly subjects but tmax, Cmax and CL/f were not altered. However, after adjusting the parameters to allow for the different average body weights of the two groups, Cmax and CL/f became significantly different (+29% and -30%, respectively). AUC(0----24 h) was increased by 41%. The changes of up to 41% in pharmacokinetic parameters were smaller than the alterations of 50-100% usually seen when titrating doses of antihypertensive drugs. The clinical relevance of the effects was not examined, but similar changes have been reported for other beta-blockers which did not appear to be clinically relevant and did not affect the dosage required to treat hypertension.