¹Department of Pharmacology and Clinical Investigation Center, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Pierre et Marie Curie University, and Unité 538 of the Institut National de la Santé et de la Recherche Médicale (INSERM), Saint-Antoine Paris VI University, Paris; and Epidauros Biotechnologie AG, Bernried.

Correspondence: Laurent Becquemont, MD, PhD, Service de Pharmacologie, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, 27 Rue de Chaligny, 75012 Paris, France. E-mail: laurent.becquemont@chusa.jussieu.fr

^*Supported by a grant from the Délégation Régionale de la Recherche Clinique d'Ile de France, Assistance Publique-Hôpitaux de Paris (Contrat CRIC-2001), and by the Institut National de la Santé et de la Recherche Médicale and the Assistance Publique-Hôpitaux de Paris, Clinical Investigation Center, Saint-Antoine Hospital.

Received 5 June 2002; Accepted 3 September 2002.

Abstract

Background: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate.

Objectives: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T).

Material and methods: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects.

Results: Dipyridamole inhibited [³H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 1.5 mol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P < .05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 1.2 ng h mL^-1 versus 6.1 0.8 ng h mL^-1 and 20.2 2.1 ng h mL^-1 versus 16.8 1.7 ng h mL^-1, respectively (P < .05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes.

Conclusion: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.