Limited value of the urinary phenytoin metabolic ratio for the assessment of cytochrome P4502C9 activity in vivo.
Relationships between the ratio of p-hydroxyphenytoin (p-HPPH), the major metabolite of phenytoin, to unchanged phenytoin excreted in urine (the urinary metabolic ratio or MR) were compared with a number of indices of the metabolic clearances of phenytoin and tolbutamide published previously for seventeen subjects separately administered these known cytochrome P4502C9 (CYP2C9) substrates. Significant correlations (rs = 0.50-0.60, P < 0.05) were observed between the phenytoin MR, derived from either 0-24 or 24-48 h urine collections, and inverse areas under the plasma unbound concentration-time curves (measured over various time intervals) of phenytoin and with plasma unbound tolbutamide clearance. Significant correlations (rs = 0.59-0.74) were also observed between the phenytoin MRs and metabolic unbound clearances for p-hydroxyphenytoin formation. Despite the significant correlations, variability in tolbutamide and phenytoin metabolic clearance parameters tended to account for < 50% of the variability in phenytoin MR. Correlations between the renal clearance of phenytoin and the phenytoin MRs suggest that variability in the renal clearance of unchanged drug limits the usefulness of the phenytoin MR for the investigation of factors influencing CYP2C9 activity in vivo.
Tassaneeyakul
W
W
Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park, South Australia.
Birkett
D J
DJ
Pass
M C
MC
Miners
J O
JO
D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000652:urine*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D015415:Biomarkers; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D008297:Male; D010672:Phenytoin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine*; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014044:Tolbutamide / Q000493:pharmacokinetics
D000927:Anticonvulsants; D015415:Biomarkers; D007004:Hypoglycemic Agents; C001419:hydroxyphenytoin; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase