S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin.
Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4-OH-debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators of S-mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs = 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population.
Sanz
E J
EJ
Department of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Sweden.
Villén
T
T
Alm
C
C
Bertilsson
L
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003647:Debrisoquin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006827:Hydantoins / Q000493:pharmacokinetics*; D006900:Hydroxylation; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008297:Male; D008617:Mephenytoin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010641:Phenotype; D013548:Sweden
D006827:Hydantoins; D007546:Isoquinolines; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin; D003647:Debrisoquin