The use of single-sample clearance estimates to probe hepatic drug metabolism in rats. IV. A model for possible application to phenotyping xenobiotic influences on human drug metabolism.
1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multi-sample estimates of clearance for carbamazepine, quinidine, and paracetamol. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates (CL) corresponded closely to multi-sample clearance estimates. Best post-dose sampling times were: carbamazepine, 3 h; quinidine, 10 h; and paracetamol, 6 h. 2. Single sample clearance estimates, CL, were calculated for seven drugs employed as probes of hepatic drug-metabolizing activity in rats. Valproic acid was investigated as a probe of microsomal and peroxisomal oxidases; antipyrine, theophylline, ethosuximide, carbamazepine and quinidine as probes of hepatic mixed-function oxidases (MFO), and paracetamol as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely, probe CL after xenobiotic pretreatment divided by control probe CL) was calculated for each probe. Eight pretreatments were used: phenobarbital (PB), beta-naphthoflavone (beta NF), polychlorinated biphenyls (PCB), rifampin, pregnenolone-16 alpha-carbonitrile (PCN), clofibric acid, cimetidine, and piperonyl butoxide. The effect of each xenobiotic pretreatment on all probe CL values was consolidated and plotted as the logarithm of the CI, and a distinct pattern or handprint evolved for each pretreatment. 4. We conclude that the use of multiple single-sample probes of hepatic MFO activity can be useful in structuring handprints to characterize xenobiotic-mediated effects on hepatic MFO. This minimally invasive in vivo approach may have application in investigating and possibly phenotyping MFO activity in human subpopulations that are subject to sustained exposure to particular xenobiotics.
Bachmann
K A
KA
Department of Pharmacology, College of Pharmacy, University of Toledo, Ohio 43606.
D000818:Animals; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D015262:Xenobiotics / Q000494:pharmacology*
D004364:Pharmaceutical Preparations; D015262:Xenobiotics; D006899:Mixed Function Oxygenases