Influence of rifampicin, phenobarbital and cimetidine on mixed function monooxygenase in extensive and poor metabolizers of debrisoquine.
The effect of enzyme induction by rifampicin and phenobarbital and enzyme inhibition by cimetidine on the hepatic mixed-function monooxygenase (MFO) was investigated in 11 non-smokers, healthy male volunteers. Five were classified as extensive metabolizers (EM) of debrisoquine and 6 as poor metabolizers (PM). Rifampicin (600 mg/day), phenobarbital (100 mg/day) and cimetidine (1.2 g/day) were given for 8, 14 and 4 days, respectively. In PM on rifampicin, the debrisoquine metabolic ratio (MR) was significantly reduced, even reaching a value less than 12.6 in 2 subjects but on phenobarbital and cimetidine, the MR was not significantly modified. In PM on rifampicin and phenobarbital, the urinary excretion of 6 beta-hydroxycortisol was significantly enhanced but not in EM on these drugs. In both groups on cimetidine, salivary antipyrine half-life was lengthened and on rifampicin, it was shortened. In EM and PM on cimetidine, the total oral clearance of antipyrine was lowered but on rifampicin it was solely increased in PM. Regarding the metabolic clearance to the three main urinary antipyrine metabolites, that of norantipyrine (NORA) was significantly increased in PM on rifampicin. In PM on cimetidine, the metabolic clearance of NORA and hydroxymethylantipyrine (HMA) was reduced but in EM that of hydroxyantipyrine was additionally decreased. In PM on rifampicin, the induction of the hepatic mixed-function oxidase system, assessed by the urinary excretion of 6 beta-hydroxycortisol, the salivary antipyrine half-life and total oral clearance and the metabolic clearance of urinary NORA, were shown. On the other hand in PM, cimetidine, a probe drug used for inhibition of the MFO system, made it impossible to distinguish PM from EM.
Leclercq
V
V
Laboratoire de Pharmacothérapie, Université Catholique de Louvain, Bruxelles, Belgium.
Desager
J P
JP
Horsmans
Y
Y
Van Nieuwenhuyze
Y
Y
Harvengt
C
C
D000328:Adult; D000983:Antipyrine / Q000378:metabolism / Q000493:pharmacokinetics; D001711:Biotransformation; D002927:Cimetidine / Q000494:pharmacology*; D003647:Debrisoquin / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D007546:Isoquinolines / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D010641:Phenotype; D012293:Rifampin / Q000494:pharmacology*
D007546:Isoquinolines; D002927:Cimetidine; D006899:Mixed Function Oxygenases; D000983:Antipyrine; D012293:Rifampin; D003647:Debrisoquin; D010634:Phenobarbital