Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo.
OBJECTIVE
To study the extent of in vivo inhibition by the antimalarial drug amodiaquine, its active metabolite N-desethylamodiaquine, or both, of the metabolism of four probe drugs of the enzymes CYP2D6, CYP2C19, CYP2C9 and CYP1A2.


METHODS
Twelve healthy Swedish volunteers received a cocktail of four probe drugs (debrisoquine, omeprazole, losartan and caffeine) to determine their baseline metabolic capacities. After a washout period, they received a 600 mg oral dose of amodiaquine hydrochloride; and 2-3 h later the cocktail was administered again. One week after the intake of amodiaquine, the subjects received the cocktail a third time. The levels of probe drugs and their metabolites as well as amodiaquine and its metabolite were determined by HPLC.


RESULTS
Plasma levels of amodiaquine and N-desethylamodiaquine could be followed in all subjects for 6 h and 28 days, respectively. Among the 12 subjects, a 3-fold variation in amodiaquine AUC and a 2-fold variation in N-desethylamodiaquine AUC, were observed. The CYP2D6 and CYP2C9 activities of the subjects were measured by debrisoquine and losartan phenotyping tests, respectively. There were significant mean increases in debrisoquine metabolic ratio (MR) between baseline and the second cocktail [MR(2 h)-MR(baseline) 1.426 (95% confidence interval 1.159, 1.755), P=0.002; ANOVA, Fisher LSD test] and in mean losartan MR between baseline and the second cocktail [MR(2 h)-MR(baseline) 1.724 (95% confidence interval 1.076, 2.762), P=0.026; ANOVA, Fisher LSD test]. The effects on CYP2D6 and CYP2C9 activities subsided within a week after intake of amodiaquine as tested by the phenotyping cocktail. The changes in omeprazole MRs and caffeine MRs were not statistically significant between any of the study phases.


CONCLUSIONS
A single dose of amodiaquine decreased CYP2D6 and CYP2C9 activities significantly compared to baseline values. Amodiaquine has the potential to cause drug-drug interactions and should be further investigated in malarial patients treated with drug combinations containing amodiaquine.
Wennerholm
Agneta
A
Division of Clinical Pharmacology C1:68, Karolinska University Hospital - Huddinge, SE-141 86, Stockholm, Sweden.
Nordmark
Anna
A
Pihlsgård
Maria
M
Mahindi
Margarita
M
Bertilsson
Leif
L
Gustafsson
Lars L
LL
D000284:Administration, Oral; D000328:Adult; D000655:Amodiaquine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D000962:Antimalarials / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D016001:Confidence Intervals; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003647:Debrisoquin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006801:Humans; D019808:Losartan / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D008875:Middle Aged; D010641:Phenotype; D013997:Time Factors
D000959:Antihypertensive Agents; D000962:Antimalarials; D000655:Amodiaquine; C047386:desethylamodiaquine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D019808:Losartan; D003647:Debrisoquin