Intestinal Absorption of Drugs in Rats with Glycerol-Induced Acute Renal Failure

• Published in: Chem. Pharm. Bull Vol. 36; no. 5; pp. 1847 - 1856
• Main Authors: KOBAYASHI, AKIRA, KIMURA, TOSHIKIRO, MORI, MASAHARU, NAKAYAMA, TAIJI, KAWAI, YUKICHI, AWAI, MICHIYASU, KOBAYASHI, MIYOKO, KUROSAKI, YUJI, NUMATA, KANAE
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01.05.1988; 公益社団法人日本薬学会; Maruzen; Japan Science and Technology Agency
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Animals; Biological and medical sciences; brush border membrane; drug absorption; electron microscopy; General pharmacology; Glycerol; Intestinal Absorption; Male; Medical sciences; Pharmaceutical Preparations - metabolism; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; polyethylene glycol 1000; poorly-absorbable drug; rat small intestine; Rats; Rats, Inbred Strains; renal failure; unstirred water layer; well-absorbable drug; Drug; Urinary system disease; Rat; Digestive system; Acute; Rodentia; Gut; Glycerol; Molecular weight; Vertebrata; Experimental disease; Mammalia; Absorption; Animal; Renal failure; Mechanism of action; Pharmacokinetics; Comparative study
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.36.1847

The intestinal absorption of drugs was investigated in rats with glycerol-induced renal failure by an in situ loop method. Drugs examined were poorly-absorbable drugs (sulfanilic acid, procainamide ethobromide, cefazolin and sulfaguanidine), well-absorbable drugs (sulfisoxazole, quinine, salicyclic acid and impramine), actively-transported drugs (cefadroxil and cyclacillin) and water-soluble, high-molecular-weight compounds (polyethylene glycol (PEG) 1000, PEG 1500 and fluorescein isothiocyanate-conjugated dextran with a molecular weight of 4000). The absorption of all the low-molecular-weight drugs was significantly increased in the renal failure group, regardless of the absorption characteristics. The enhancement of membrane permeability was also observed by an in vitro cannulated everted sac method. The investigation of membrane permeability to high-molecular-weight compounds with PEG 1000 and 1500 showed that the enhancement of membrane permeability in the renal failure state was limited to molecules whose molecular weights were lower than about 1000. Furthermore, the enhancement of membrane permeability was seen in the brush border membrane vesicles prepared from the small intestine of rats with renal failure, although lipid fluidity, as assessed by steady-state fluorescence polarization techniques using 1, 6-diphenyl-1, 3, 5-hexatriene as a probe was not changed in brush border membranes of the diseased rat. On the other hand, a reduction of thickness of the unstirred water layer adjacent to the membrane was observed. Examination by transmission electron microscopy revealed blebs at the tip of microvilli and the thickness of the glycocalyx was reduced. Possible mechanisms of the increase in drug absorption are discussed separately for poorly-absorbable and well-absorbable drugs.