The influence of active secretion processes on intestinal absorption of salbutamol in the rat.
Salbutamol was perfused in the small intestine of rat using a standard rat gut "in situ" preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0mM); (2) at a 0.29mM concentration - thought to be close to the allometric dose in man - in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0mM); and (3) at 0.29mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0mM). In free solution, the mixed-order rate constants, k'(a), of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation of enzymatic systems responsible for the secretion of the drug from the enterocyte to the luminal fluid, a process that could explain the poor absorption of salbutamol. In the presence of sodium azide, the k(a) values increased about 1.5-fold, whereas in the presence of verapamil they increased two- to three-fold. These results indicate that salbutamol can act as a substrate of an intestinal secretory transport, which probably includes--at least in part--the enzyme P-glycoprotein, since verapamil has been shown to inhibit this enzyme by dose-dependent competition. This leads to a secretion-limited peroral absorption of salbutamol, which contributes to the poor oral bioavailability of the drug. The possible options for improving salbutamol absorption are discussed.
Valenzuela
B
B
Department of Pharmacy and Pharmaceutics, Faculty of Pharmacy, University of Valencia, Avd. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
Nácher
A
A
Casabó
V G
VG
Martín-Villodre
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000493:pharmacokinetics*; D000420:Albuterol / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007408:Intestinal Absorption; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D019810:Sodium Azide / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000318:Adrenergic beta-Agonists; D019810:Sodium Azide; D014700:Verapamil; D000420:Albuterol