Lack of polymorphism of the conversion of losartan to its active metabolite E-3174 in extensive and poor metabolizers of debrisoquine (cytochrome P450 2D6) and mephenytoin (cytochrome P450 2C19).
OBJECTIVE
Losartan was given to subjects with known phenotypes of the polymorphic enzymes CYP2D6 and CYP2C19 to study any possible influence on the metabolism of the drug.


METHODS
Plasma concentrations of losartan and E-3174 were studied after oral intake of 50 mg losartan in 24 healthy, male, Swedish Caucasian subjects who were extensive or poor metabolizers (EM/PM) of debrisoquine [cytochrome P450 2D6 (CYP2D6)] or mephenytoin [cytochrome P450 2C19 (CYP2C19)].


RESULTS
The areas under the curve (AUCinfinity) of losartan and E-3174 did not differ between poor and extensive metabolizers of debrisoquine or mephenytoin, respectively.


CONCLUSIONS
About 14% of the antihypertensive drug losartan is metabolized to the active carboxylic acid metabolite E-3174, which contributes to the effect of losartan. The present study suggests that CYP2D6 and CYP2C19 are not involved to any major extent in the in vivo conversion of losartan to E-3174.
Sandwall
P
P
Department of Clinical Research, Merck Sharp & Dohme (Sweden) AB, Sollentuna.
Lo
M W
MW
Jonzon
B
B
Dalén
P
P
Furtek
C
C
Ritter
M
M
Alván
G
G
McCrea
J
J
Sjöqvist
F
F
D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism*; D006801:Humans; D019808:Losartan / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011110:Polymorphism, Genetic
D000959:Antihypertensive Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D019808:Losartan; D008617:Mephenytoin; D003647:Debrisoquin