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Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.

Ketoconazole is an oral imidazole antifungal agent useful in the treatment of opportunistic fungal infections. Gastrointestinal absorption of this agent is variable and dependent on the presence of gastric acid. This study compared the effects of concomitant sucralfate administration with ranitidine administration on the pharmacokinetic disposition of a 400-mg ketoconazole dose. Six healthy male volunteers were randomized to receive 400 mg of ketoconazole alone, 1.0 g of sucralfate concomitantly with a 400-mg ketoconazole dose, or ranitidine, administered 2 h prior to a 400-mg ketoconazole dose to titrate to a gastric pH of 6. All subjects received all three regimens in crossover fashion. Gastric pH was measured continuously for 4 h after ketoconazole administration in all subjects by using a Heidelberg radiotelemetry pH capsule. Relative ketoconazole bioavailability was compared between treatments. With sucralfate, five of six subjects demonstrated a decrease in the peak drug concentration in serum as well as an increase in the time to peak concentration, indicating a delay in ketoconazole absorption. The mean area under the concentration-time curve from 0 to 12 h for ketoconazole following gastric alkalinization was significantly different from that of either ketoconazole alone or ketoconazole with sucralfate (P < 0.01). Continuous gastric pH monitoring allowed correlation between the decrease in ketoconazole bioavailability observed with ranitidine and the increase in gastric pH. The apparent decrease in ketoconazole bioavailability observed with sucralfate appears to be caused by an alternative mechanism since a change in gastric pH was not observed. On the basis of these findings, separating the administration of ketoconazole and sucralfate should be considered to decrease the potential for interaction of sucralfate on ketoconazole bioavailability.

Bevirimat (BVM; formerly known as PA-457) is a novel inhibitor of human immunodeficiency virus (HIV)maturation that is being developed for the treatment of HIV infection. The pharmacokinetics of this agent in healthy male volunteers were studied in a randomized, double-blind study in which the participants received single oral doses of placebo (n ‫؍‬ 8) or escalating doses of BVM at 25, 50, 100, or 250 mg (n ‫؍‬ 6 per dose); escalation was performed only after the pharmacokinetics and safety of the preceding dose had been evaluated. Plasma was collected over 480 h after dosing and urine was collected over 48 h after dosing for determination of the values of pharmacokinetic parameters. BVM was well absorbed after oral administration, with peak plasma concentrations being achieved 1 to 3 h after dosing. The half-life was 60 to 80 h. The exposure assessed by determination of the peak concentration and the area under the concentration-time curve was dose proportional. Single oral doses of BVM were well tolerated: there were no dose-limiting toxicities, and no serious adverse events were reported. These findings suggest that that BVM offers a favorable pharmacokinetic profile, with predictable pharmacokinetics following the oral administration of single doses. The long half-life of BVM may facilitate once-daily dosing.Although the introduction of highly active antiretroviral therapy regimens has significantly improved the prognosis for people infected with human immunodeficiency virus (HIV) type 1 (HIV-1) (2, 9), the development of viral resistance presents a major clinical challenge. It is estimated that up to 78% of individuals with HIV-1 infection harbor drug-resistant strains (10) and that 5 to 10% of strains are resistant to all classes of reverse transcriptase and viral protease inhibitors (4). The growing problem of resistance necessitates the development of new agents and regimens for the control of HIV infection (1). One response to this need has been to investigate therapeutic targets other than reverse transcriptase and viral protease, which have traditionally been the targets of highly active antiretroviral therapy regimens.Bevirimat (BVM; formerly known as PA-457) [3-O-(3Ј,3Ј-dimethylsuccinyl)betulinic acid] (Fig. 1) is the first of a new class of antiretroviral agents that inhibit HIV-1 replication by disrupting virus maturation. BVM inhibits the final step in the Gag processing cascade, resulting in defective core condensation and the release of noninfectious virus particles from HIV-1-infected cells, thus blocking the spread of the infection to new cells (5). Due to this novel mechanism of action, BVM shows potent activity against HIV-1 strains that are resistant to all currently approved classes of antiretroviral agent (3).In vitro studies have shown that BVM does not undergo oxidative metabolism in human microsomes, does not inhibit the cytochrome P450 system, and does not interact with human Pgp (6). It is a substrate for UDP-glucuronosyltransferases, and since it contains two carboxylic acid moiet...