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Antimicrobial Agents and Chemotherapy, February 2002, p. 458-463, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.458-463.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

F. De Bony,1 M. Tod,2 R. Bidault,1* N. T. On,1 J. Posner,1 and P. Rolan1

Department of Clinical Pharmacology, Glaxo Wellcome Research and Development Laboratory, Greenford, United Kingdom,1 Department of Pharmacotoxicology, Hôpital Avicenne, Bobigny, France2

Received 11 January 2001/ Returned for modification 16 August 2001/ Accepted 28 October 2001

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 (Cmax) 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 Cmax 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.

* Corresponding author. Mailing address: Service de Pharmacologie Clinique, Laboratoire Glaxo Wellcome, 100, route de Versailles, 78163 Marly-le-Roi, France. Phone: 33 (1) 39.17.88.27. Fax: 33 (1) 39.17.86.87. E-mail: rb47479{at}glaxowellcome.co.uk.

Antimicrobial Agents and Chemotherapy, February 2002, p. 458-463, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.458-463.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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