Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats.

BACKGROUND AND PURPOSE: Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. EXPERIMENTAL APPROACH: Two groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg(-1) racemic warfarin i.v., and the test group (n = 13) 1 mg·kg(-1) of racemic warfarin followed by 25 mg·kg(-1) ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. KEY RESULTS: ETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. CONCLUSION AND IMPLICATIONS: Our data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance.

Lack of pharmacokinetic interaction between dipyridamole and zalcitabine in rats.

Resistance usually manifests following long-term dideoxynucleoside therapy of HIV-1 infection. This period appears to coincide with reduced dosage regimens. Resistance that is associated with long-term monotherapy may, in part, be due to decreased intracellular drug concentrations. It has been reported that intracellular uptake of the dideoxynucleosides is enhanced by dipyridamole. Hence, dipyridamole may potentially be used to optimize the effects of zalcitabine in HIV-1 antiretroviral "cocktail". The purpose of this study was to characterize the pharmacokinetics of zalcitabine when administered alone and concomitantly with dipyridamole. Also, we determined, indirectly, whether dipyridamole modulated the intracellular uptake of zalcitabine. Rats were intravenously administered either zalcitabine 100 mg/kg alone or with dipyridamole 15 mg/kg. Except renal clearance (CIR), there were no statistically significant differences in the pharmacokinetic parameters including the steady-state volume of distribution and distribution coefficient. Zalcitabine plasma concentrations declined rapidly in a bi-exponential fashion, with a terminal half-life of 1.03 +/- 0.18 hr. alone versus 1.08 +/- 0.22 hr. with dipyridamole. The area under the concentration-time curve was not significantly different with or without dipyridamole. ClR, was 1.42 +/- 0.37 l/hr./kg for zalcitabine alone versus 1.09 +/- 0.28 l/hr./kg with dipyridamole. Our single dose study show that zalcitabine disposition kinetics were not significantly modulated by dipyridamole.

Pharmacokinetics of 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rats.

Although several drugs have shown clinical anti-human immunodeficiency virus activity, reduced activity with long-term use and toxicity make new agents with high therapeutic indices desirable. Racemic cis-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) is a new synthetic nucleoside analogue that is usually potent against human immunodeficiency virus types 1 and 2 and hepatitis B virus in vitro. The purpose of this study was to characterize the preclinical pharmacokinetics of FTC in rats. Rats were administered 10, 50, and 100 mg of FTC per kg of body weight intravenously. Concentrations of FTC in plasma and urine were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma FTC concentrations declined rapidly in a biexponential fashion, with a terminal half-life of approximately 2 h. The area under the plasma FTC concentration-time curve increased proportionally with increasing dose, and there were no statistically significant differences in pharmacokinetic parameters among the three doses. Thus, the disposition of FTC was independent of dose over the range of 10-100 mg/kg. Since the disposition of FTC was linear, pharmacokinetic parameters were averaged for the three doses. The average total clearance of FTC was 1.91 +/- 0.32 L/h/kg (mean +/- SD), the average renal clearance was 1.08 +/- 0.26 L/h/kg, and the average nonrenal clearance was 0.83 +/- 0.27 L/h/kg. Approximately 55% of the dose of FTC was recovered as unchanged drug in the urine. The steady-state volume of distribution of FTC averaged 2.17 +/- 0.59 L/kg.

Potential use of aldose reductase inhibitors to prevent diabetic complications.

Reviewed are (1) the biochemical basis and pathophysiology of diabetic complications and (2) the structure-activity relationships, pharmacology, pharmacokinetics, clinical trials, and adverse effects of aldose reductase inhibitors (ARIs). ARIs are a new class of drugs potentially useful in preventing diabetic complications, the most widely studied of which have been cataracts and neuropathy. ARIs inhibit aldose reductase, the first, rate-limiting enzyme in the polyol metabolic pathway. In nonphysiological hyperglycemia the activity of hexokinase becomes saturated while that of aldose reductase is enhanced, resulting in intracellular accumulation of sorbitol. Because sorbitol does not readily penetrate the cell membrane it can persist within cells, which may lead to diabetic complications. ARIs are a class of structurally dissimilar compounds that include carboxylic acid derivatives, flavonoids, and spirohydantoins. The major pharmacologic action of an ARI involves competitive binding to aldose reductase and consequent blocking of sorbitol production. ARIs delay cataract formation in animals, but the role of aldose reductase in cataract formation in human diabetics has not been established. The adverse effects of ARIs include hypersensitivity reactions. Although the polyol pathway may not be solely responsible for diabetic complications, studies suggest that therapy with ARIs could be beneficial. Further research is needed to determine the long-term impact and adverse effects of ARIs in the treatment of diabetic complications.