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Characterization of Gastrointestinal Drug Absorption in Cynomolgus Monkeys

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Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan, Faculty of Pharmaceutical Science, Tokyo University of Pharmacy and Life Science, Tokyo, Japan, and Faculty of Pharmaceutical Science, Setsunan University, Osaka, Japan
* Corresponding author. Mailing address: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Tel: 81-3-3492-3131 . Fax: 81-3-5436-8567. E-mail: [email protected]
†Daiichi Sankyo Co., Ltd.
‡Tokyo University of Pharmacy and Life Science.
§Setsunan University.
Cite this: Mol. Pharmaceutics 2008, 5, 2, 340–348
Publication Date (Web):February 2, 2008
https://doi.org/10.1021/mp700095p
Copyright © 2008 American Chemical Society

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    Abstract

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    Possible factors of species differences in gastrointestinal drug absorption between cynomolgus monkeys and humans were examined using several commercial drugs. Oral bioavailability (BA) of acetaminophen, furosemide, and propranolol in cynomolgus monkeys was significantly lower than that in humans. From the pharmacokinetic analysis, these drugs were found to show the low fraction absorbed into portal vein (FaFg), suggesting that the low BA in cynomolgus monkeys was attributed mainly to the gastrointestinal absorption processes. The gastric emptying rate (GER) calculated from plasma concentration profiles after oral administration of acetaminophen in cynomolgus monkeys was similar in humans. The gastrointestinal transit time (GITT) in cynomolgus monkeys was only slightly shorter than that in humans. On the other hand, it was demonstrated that the apparent intestinal permeability (Papp) of five drugs to cynomolgus monkey intestine was lower than that to rat intestine; especially propranolol and furosemide showed the remarkably low Papp. The expression levels of mRNAs of efflux transporters analyzed by real-time RT-PCR indicated that mRNA expression levels of MDR1, MRP2, and BCRP in monkey intestine were significantly higher than those in human intestine. This result suggested that low oral absorption of furosemide in cynomolgus monkeys was attributed to the high activities of efflux transporters in its intestinal membrane. Results of in vivo PK analysis clearly showed that FaFg values of propranolol and acetaminophen in cynomolgus monkeys were markedly lower than those in humans. Since propranolol and acetaminophen were the drug with high membrane permeability, it was considered that the high first-pass metabolism in the enterocytes was a main factor of their low FaFg in cynomolgus monkeys. In conclusion, it was demonstrated that the high activities of efflux transporters and/or metabolizing enzymes in the intestinal membrane are possible factors to cause poor oral absorption of drugs in cynomolgus monkeys.

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