THE EFFECT OF CARBON MONOXIDE INHALATION ON IN VIVO DRUG METABOLISM IN THE RAT

¹ Department of Environmental Medicine, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland

Previous studies have shown that the cytochrome P-450-containing hepatic mixed function oxidase system is inhibited in vitro by carbon monoxide (CO). This study reports that acute exposure to CO resulted in inhibition of in vivo drug metabolism in rats as measured by prolonged response to two drugs, hexobarbital and zoxazolamine. Exposure to CO for 90 minutes followed by drug testing in room air resulted in a significantprolongation of response to hexobarbital at a CO concentration of 1000 ppm and a significant prolongation of response to zoxazolamine at a CO concentration of 250 ppm. Exposure to the same CO levels for 90 minutes followed by drug testing in the CO environment resulted in significant enhancement of the CO-induced effect. The prolongation of the pharmacologic responses could be explained by a CO-induced inhibition of the hepatic mixed function oxidase enzyme system responsible for the metabolism of these compounds. Inhalation of atmospheres containing lowered O₂ concentrations also inhibited zoxazolamine metabolism. The data do not, as yet, allow a final conclusion to be made concerning the mechanism of the CO-induced effect, i.e., whether it is due to the direct effect of CO on P-450 or, alternatively, to an indirect effect of the induced tissue hypoxia. However, an initial approach to this problem has been made by establishing the concentrations of CO and lowered inspired O₂ required to produce equivalent alterations in drug metabolism.

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