HEPATIC AND EXTRAHEPATIC METABOLISM OF SALBUTAMOL IN ANESTHETIZED RABBITS

Orally administered salbutamol undergoes an extensive first-pass effec t. This study investigated the roles of the intestine (INT), liver (HE P), and lung (LUN) in salbutamol extraction. Salbutamol was administer ed to live groups of anesthetized rabbits by the following routes: int raduodenal (ID) (800 mug/kg), intraportal (IP), (60 mug/kg), intrajugu lar (IV) (60 gg/kg), endotracheal (ET) (60 mug/kg), and intra-arterial (IA) (60 mug/kg). Multiple blood samples were drawn and the areas und er salbutamol plasma concentrations-time curves (AUCs) were calculated . Since IA salbutamol administration generated 100% bioavailability (F ), AUC. was used as a reference for comparison. Salbutamol F values fo r the ID, IP, IV, and ET routes were 0.013, 0.15, 0.53, and 0.53, resp ectively. The ratio of the AUC of salbutamol administered before the o rgan (ID, IP, IV, or ET) to the AUC estimated when given after the org an (IP, IV, and IA) allowed assessment of the extraction ratio (E) of INT, HEP, and LUN, respectively. E(INT) was 0.92, E(HEP) WaS 0.71, and E(LUN) was 0.47. The mean ratio of the AUC of the metabolite (AUC(M)) over the AUC of the parent compound was 704 +/- 77 for the ID, compar ed with 83 +/- 12 for the IP, 11 +/- 1 for the IV, 1.7 +/- 0.3 for the ET routes, and 4 +/- 1 for the IA routes. On the other hand, when the AUC(M) was normalized by the dose, this ratio was INT = HEP > LUN, su ggesting that the ability of INT to conjugate salbutamol is not very i mportant. These results demonstrate that: 1) several organs contribute to salbutamol first-pass, with INT showing the highest extraction rat io, followed by HEP and LUN; 2) salbutamol's systemic availability is influenced by its route of administration; and 3) salbutamol first-pas s generates considerable amounts of conjugated and unconjugated metabo lites.