The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects

• Published in: Clinical pharmacology and therapeutics Vol. 66; no. 4; p. 408
• Main Authors: van Agtmael, M A, Gupta, V, van der Graaf, C A, van Boxtel, C J
• Format: Journal Article
• Language: English
• Published: United States 01.10.1999
• Subjects: Administration, Oral; Adult; Antifungal Agents - administration & dosage; Antifungal Agents - blood; Antifungal Agents - pharmacokinetics; Antimalarials - administration & dosage; Antimalarials - blood; Antimalarials - pharmacokinetics; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - blood; Antiprotozoal Agents - pharmacokinetics; Artemisinins; Beverages; Biological Availability; Citrus; Cross-Over Studies; Food-Drug Interactions; Humans; Male; Reference Values; Sesquiterpenes - administration & dosage; Sesquiterpenes - blood; Sesquiterpenes - pharmacokinetics; Time Factors
• ISSN: 0009-9236
• DOI: 10.1053/cp.1999.v66.a101946

Artemether is a new and effective treatment for malaria, although relapse is a problem in monotherapy. These relapses could be related to a time-dependent decline in artemether plasma levels described in multiple-dose studies and probably caused by autoinduction. The aim of this study was to evaluate the effect of grapefruit juice on the decreasing bioavailability over time of artemether. In a randomized, two-phase crossover study, eight healthy male subjects took 100 mg oral artemether with 350 mL water or with 350 mL double-strength fresh frozen grapefruit juice once daily for 5 days. On day 1 and day 5, 17 blood samples were collected over a period of 8 hours. The mean peak artemether plasma concentration (Cmax) and the mean area under the concentration-time curve (AUC) after the last dose at day 5 were about one third compared with day 1, without a change in the elimination half-life after intake with water (P = .006 for Cmax; P = .005 for AUC) and with grapefruit juice (P < .001 for Cmax and AUC). Grapefruit juice increased Cmax (P = .021) and AUC (P < .001) twofold on day 1 (P = .021) and day 5 (P = .05 for Cmax; P = .004 for AUC). Dihydroartemisinin, the active metabolite, showed a twofold increase in Cmax (P = .006) and AUC (P = .001) with grapefruit juice, without time-dependent changes of pharmacokinetic parameters. Grapefruit juice significantly increased the oral bioavailability of artemether but did not prevent the time-dependent reduction in bioavailability. It suggests that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether but seems to not be involved in the autoinduction process.