EXPIRATORY MEASUREMENT OF MAXIMAL AMINOPYRINE DEMETHYLATION INVIVO - EFFECT OF PHENOBARBITAL, PARTIAL-HEPATECTOMY, PORTACAVAL-SHUNT AND BILE-DUCT LIGATION IN RAT

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  • 1 January 1976
    • journal article
    • research article
    • Vol. 196  (2) , 501-509
Abstract
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.