Formation of meprobamate from carisoprodol is catalysed by CYP2C19.
Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.
Dalén
P
P
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Alvan
G
G
Wakelkamp
M
M
Olsen
H
H
D000284:Administration, Oral; D000328:Adult; D000700:Analgesics / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D002328:Carisoprodol / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008620:Meprobamate / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009125:Muscle Relaxants, Central / Q000378:metabolism*
D000700:Analgesics; D009125:Muscle Relaxants, Central; D002328:Carisoprodol; D003577:Cytochrome P-450 Enzyme System; D008620:Meprobamate; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin; D003647:Debrisoquin