Studies on inhibition and induction of metabolism of ethyl carbamate by acetone and related compounds. Evidence for metabolism by cytochromes P-450.
Ethanol and a variety of other compounds previously have been shown to acutely inhibit the metabolism of ethyl carbamate (EC) when given concurrently in mice. On the other hand, ethanol pretreatment (10% in drinking water for the period 48 to 12 hr prior to EC treatment) is known to have the opposite effect and enhance the clearance of EC from blood of mice. In the present work, acetone has been shown to act similarly. Concurrent acetone treatment inhibits the metabolism of EC (11.1 mg/kg po) in male A/JAX mice in a dose-response manner. Blood clearance (Cl) of this po dose of EC from mice following concurrent acetone treatment (50 mg/kg, 0.86 mmol/kg ip) averaged 185 +/- 5.4 (SE) ml hr-1 kg-1 vs. controls of 804 +/- 24.6 ml hr-1 kg-1. Comparing doses that produce equal effects on the blood clearance values of EC, acetone is approximately 50-fold more potent as an inhibitor than ethanol. Pretreatment of mice with acetone (2 g/kg ip) 48 hr and 24 hr before EC administration po increased the clearance of EC approximately 3-fold (CI = 2623 +/- 123 ml hr-1 kg-1). 2-Propanol was found to be at least as potent as inhibitor as acetone, but with a longer duration of inhibition; this longer duration was explained by the longer persistence of acetone in blood from conversion of 2-propanol to acetone.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, KY 40292.
N
N
Kurata
H E
HE
Hurst
F W
FW
Benz
R A
RA
Kemper
W J
WJ
Waddell
D000433:1-Propanol / Q000097:blood; D000096:Acetone / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000431:Ethanol / Q000097:blood; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D013311:Streptozocin / Q000378:metabolism / Q000652:urine; D014520:Urethane / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D000096:Acetone; D014520:Urethane; D000431:Ethanol; D013311:Streptozocin; D003577:Cytochrome P-450 Enzyme System; D000433:1-Propanol