Expiratory measurement of maximal amino-pyrine demethylation in vivo: effect of phenobarbital, partial hepatectomy, protacaval shunt and bile duct ligation in the rat.
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 and Kd of 26 mumol/100 g could be calculated. Enzyme induction with phenobarbital increased Vmax to 745 nmol/min/100 g, whereas in the rat with portacaval shunt, it was reduced to 45 nmol/min/100 g. After 48-hour bile duct ligation, Vmax was not significantly different from the controls, but Kd increased to 36 mumol/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.
D000632:Aminopyrine / Q000378:metabolism*; D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects; D002245:Carbon Dioxide / Q000378:metabolism; D006498:Hepatectomy; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology*; D011167:Portacaval Shunt, Surgical; D051381:Rats; D013997:Time Factors
D000632:Aminopyrine; D002245:Carbon Dioxide; D010634:Phenobarbital