Expiratory measurement of maximal amino-pyrine demethylation in vivo: effect of phenobarbital, partial hepatectomy, protacaval shunt and bile duct ligation in the rat
Lauterburg, B.H.; Bircher, J.
Journal of Pharmacology and Experimental Therapeutics 196(2): 501-509
1976
ISSN/ISBN: 0022-3565 PMID: 1255494 Document Number: 103325
Current in vivo methods do not give information about the drug-metabolizing capacity (Vmax) and the affinity of the microsomal enzyme system for the drug, i.e., the dose yielding Vmax/2 (Kd). To explore the possibility of estimating these variables from demethylation rates measured by 14CO2 exhalation, various doses of 14C-aminopyrine were injected i.v. to unanesthetized rats. Drug clearances based on 14CO2 exhalation agreed well with those derived from plasma disappearance rates. Evaluation of dose-response curves revealed saturation phenomena. In the normal rat a Vmax of 173 nmol/min 100 g-1 and a Kd of 26 .mu.mol/100 g were calculated. Enzyme induction with phenobarbital increased Vmax to 745 nmol/min 100 g-1, whereas in the rat with portacaval shunt, it was reduced to 45 nmol/min 100 g-1. After 48-h bile duct ligation, Vmax was not significantly different from the controls, but Kd increased to 36 .mu.mol/100 g compatible with a competitive type of inhibition of aminopyrine demethylation. Two-thirds hepatectomy reduced Vmax by only 50%, suggesting that a substantial portion of demethylation occurs extrahepatically. The approach presented appears to be a valid alternative to conventional plasma clearance methods allowing interpretation of some mechanisms affecting in vivo drug metabolism under various conditions.