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The effect of grapefruit juice on the time‐dependent decline of artemether plasma levels in healthy subjects
Author(s) -
Agtmael Michiel A.,
Gupta Veenu,
Graaf Chantal A. A,
Boxtel Chris J.
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1053/cp.1999.v66.a101946
Subject(s) - grapefruit juice , cmax , bioavailability , pharmacokinetics , artemether , pharmacology , crossover study , area under the curve , chemistry , medicine , artemisinin , malaria , placebo , alternative medicine , pathology , immunology , plasmodium falciparum
Background 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. Methods 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. Results The mean peak artemether plasma concentration (C max ) 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 C max ; P = .005 for AUC) and with grapefruit juice ( P < .001 for C max and AUC). Grapefruit juice increased C max ( P = .021) and AUC ( P < .001) twofold on day 1 ( P = .021) and day 5 ( P = .05 for C max ; P = .004 for AUC). Dihydroartemisinin, the active metabolite, showed a twofold increase in C max ( P = .006) and AUC ( P = .001) with grapefruit juice, without time‐dependent changes of pharmacokinetic parameters. Conclusions 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. Clinical Pharmacology & Therapeutics (1999) 66 , 408–414; doi: 10.1053/cp.1999.v66.a101946