| Abstract: | The importance of the route of drug administration for drug ethanol interactions was studied using clomethiazole as model drug. To 10 rabbits equipped with permanently implanted catheters in the portal vein, the vena cava and the aorta respectively, clomethiazole was infused either into the portal vein or the vena cava and either together with i.v. saline or with i.v. ethanol. Arterial plasma clomethiazole and ethanol concentrations were measured by gas-liquid chromatography. After portal clomethiazole infusion, ethanol increased by the relative availability of clomethiazole to 270 +/- 90% (S.D.) of the saline controls, whereas after i.v. clomethiazole infusions the relative availability was increased only to 120 +/- 20% of the corresponding controls. Similarly, ethanol increased average plasma clomethiazole concentrations after 90 min of portal infusion from 5 to 14 nmol/ml, whereas after i.v. clomethiazole infusions the ethanol effect was small, the concentrations increasing only from 28 to 35 nmol/ml. These results are compatible with the concept that an ethanol-induced reduction of the hepatic capacity to metabolize a highly extracted drug is reflected to a much larger extent during first-pass elimination than during systemic clearance. Consequently, clinical toxicity in inebriated subjects is more likely to occur after oral than after parenteral administration of high extraction drugs. |
