The use of single sample clearance estimates to probe hepatic drug metabolism: handprinting the influence of cigarette smoking on human hepatic drug metabolism.
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Bachmann KA, Nunlee M, Martin M, Schwartz J, Jauregui L, Forney RB Jr
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Radiology
Cardiology
Neurology
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Cardiology
Neurology
Radiology
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volume
20
ISSN
0049-8254
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["Bachmann KA, Nunlee M, Martin M, Schwartz J, Jauregui L, Forney RB Jr","Antipyrine pharmacokinetics, Carbamazepine pharmacokinetics, Glucuronosyltransferase metabolism, Humans, Lorazepam pharmacokinetics, Male, Metabolic Clearance Rate, Microbodies enzymology, Microsomes, Liver enzymology, Mixed Function Oxygenases metabolism, Oxidoreductases metabolism, Polycyclic Compounds pharmacology, Quinidine pharmacokinetics, Theophylline pharmacokinetics, Valproic Acid metabolism, Liver enzymology, Pharmaceutical Preparations metabolism, Smoking metabolism","English","1990-05-01","Xenobiotica; the fate of foreign compounds in biological systems","20"]
Description
1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multiple-sample estimates of clearance for quinidine, valproic acid, unbound valproic acid, and lorazepam. When plasma concentrations were measured at various post-dose times, both individual and mean values of single-sample clearance estimates, CL, corresponded closely to multiple-sample clearance estimates. Best post-dose sampling times were: quinidine, 8 h; valproic acid, 24 h; and lorazepam, 24 h. 2. Single-sample clearance estimates, CL, were calculated for seven drugs employed as probes of human hepatic drug-metabolizing enzymes. Valproic acid was used to probe microsomal and peroxisomal beta-oxidase activity; antipyrine, phenytoin, quinidine, carbamazepine, and theophylline were used as probes of hepatic mixed-function oxidases (MFO), and lorazepam as a probe for UDP-glucuronosyltransferase activity. 3. A clearance index (CI, namely probe CL for smokers divided by probe CL for non-smokers) was calculated for each probe. The effect of cigarette smoking (and presumably polycyclic aromatic hydrocarbon exposure) on all probe CL values was consolidated and plotted as the logarithm of the CI to produce a handprint of drug metabolizing enzyme activity for cigarette smokers. 4. Only theophylline CL was significantly faster among smokers than non-smokers (P less than 0.01). 5. We conclude that the use of multiple probes of MFO activity when given in a single-dose, single-sample protocol for structuring handprints represents a minimally invasive and useful approach to characterize xenobiotic-mediated effects on hepatic MFO.
