Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir

Abstract

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C max ) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C max by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.Valaciclovir (Valtrex) is the L-valine ester of acyclovir and is extensively converted to the antiherpetic compound acyclovir by hepatic first-pass metabolism following oral administration. Its bioavailability as valaciclovir is three-to fivefold greater than acyclovir's oral bioavailability (13). The active metabolite acyclovir is excreted 85% unchanged in the urine, with the rate of renal clearance (CL R ) being three times that of the glomerular filtration rate, indicating that renal excretion has a significant tubular-secretion component. Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir. The drug interactions at the renal level were modeled as a function of the concentrations of the interaction drugs in plasma in order to characterize more precisely their mechanisms and potential consequences. MATERIALS AND METHODS Study design.We employed an open, randomized, balanced, crossover study design with four drug treatments separated by intervals of at least 1 week. Twelve healthy male volunteers (age range, 22 to 43 years; weight range, 54 to 111 kg) par...

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