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


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.
van Agtmael
M A
MA
Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
Gupta
V
V
van der Graaf
C A
CA
van Boxtel
C J
CJ
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000077549:Artemether; D037621:Artemisinins; D001628:Beverages; D001682:Biological Availability; D002957:Citrus; D018592:Cross-Over Studies; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D012016:Reference Values; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D000935:Antifungal Agents; D000962:Antimalarials; D000981:Antiprotozoal Agents; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol; D000077549:Artemether