The increased intestinal absorption rate is responsible for the reduced hepatic first-pass extraction of propranolol in rats with cisplatin-induced renal dysfunction.
The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)). ARF induced a significant increase in blood propranolol concentration after intra-intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg(-1) was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg(-1) dose was 54.7% and 81.4% in control and ARF rats, respectively. In contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first-pass extraction (E(h)) was dose-dependent and saturable: E(h) of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg(-1), respectively, and E(h) in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg(-1), respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism.
Okabe
Hiromi
H
Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Toyama 930-0194, Japan.
Mizukami
Akiko
A
Taguchi
Masato
M
Aiba
Tetsuya
T
Yasuhara
Masato
M
Hashimoto
Yukiya
Y
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002945:Cisplatin; D004305:Dose-Response Relationship, Drug; D007408:Intestinal Absorption; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D011433:Propranolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D002945:Cisplatin