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Drug Metabolism and Disposition Fast Forward
First published on December 2, 2005; DOI: 10.1124/dmd.105.007682

0090-9556/06/3403-398-404$20.00
DMD 34:398-404, 2006

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FIRST-PASS HYDROLYSIS OF A PROPRANOLOL ESTER DERIVATIVE IN RAT SMALL INTESTINE

Kenji Masaki, Megumi Taketani, and Teruko Imai

Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

To evaluate the first-pass hydrolysis of O-isovaleryl-propranolol (isovaleryl-PL), which was used as a model ester-compound, rat intestinal jejunum and blood vessels were perfused simultaneously. The membrane permeability of isovaleryl-PL was greater than that of PL because it was more lipophilic. Isovaleryl-PL was almost completely hydrolyzed to PL and isovaleric acid (IVA) in epithelial cells at a rate limited by its uptake. Based on pH partitioning, PL and IVA were transported into both vascular (pH 7.4) and luminal sides (pH 6.5). Therefore, when isovaleryl-PL was perfused into the jejunal lumen, more than 90% permeated into the blood vessel as PL. In addition, PL appeared in the lumen at a rate 6-fold greater than that in blood vessels. When isovaleryl-PL was perfused, its disappearance (50.5 ± 1.95 nmol/min) was the sum of the absorption and secretion rates of PL. In contrast, IVA was transported into blood vessels rather than the jejunal lumen. In addition, the calculated degradation clearance from in vitro hydrolysis (Km 13.7 ± 1.71 µM, Vmax 29.1 ± 3.81 nmol/min/mg protein) was 3.42 ml/min/10 cm jejunum, which was 24-fold greater than the observed degradation clearance (CLdeg) (0.14 ± 0.02 ml/min/10 cm jejunum). These findings indicate that in addition to the liver, the intestine markedly contributes to first-pass hydrolysis.

Address correspondence to: Dr. Teruko Imai, Professor, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Kumamoto, 862-0973, Japan. E-mail: iteruko{at}gpo.kumamoto-u.ac.jp




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K. Masaki, M. Hashimoto, and T. Imai
Intestinal First-Pass Metabolism via Carboxylesterase in Rat Jejunum and Ileum
Drug Metab. Dispos., July 1, 2007; 35(7): 1089 - 1095.
[Abstract] [Full Text] [PDF]


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