title: Circadian modulation in the intestinal absorption of P-glycoprotein substrates in monkeys.
abstract: Recent studies in laboratory rodents have revealed that circadian oscillation in the physiologic functions affecting drug disposition underlies the dosing time-dependent change in pharmacokinetics. However, it is difficult to predict the circadian change in the drug pharmacokinetics in a diurnal human by using the data collected from nocturnal rodents. In this study, we used cynomolgus monkeys, diurnal active animals, to evaluate the relevance of intestinal expression of P-glycoprotein (P-gp) to the dosing time dependency of the pharmacokinetics of its substrates. The rhythmic phases of circadian gene expression in the suprachiasmatic nuclei (the mammalian circadian pacemaker) of cynomolgus monkeys were similar to those reported in nocturnal rodents. On the other hand, the expression of circadian clock genes in the intestinal epithelial cells of monkeys oscillated at opposite phases in rodents. The intestinal expression of P-gp in the small intestine of monkeys was also oscillated in a circadian time-dependent manner. Furthermore, the intestinal absorption of P-gp substrates (quinidine and etoposide) was substantially suppressed by administering the drugs at the times of day when P-gp levels were abundant. By contrast, there was no significant dosing time-dependent difference in the absorption of the non-P-gp substrate (acetaminophen). The oscillation in the intestinal expression of P-gp appears to affect the pharmacokinetics of its substrates. Identification of circadian factors affecting the drug disposition in laboratory monkeys may improve the predictive accuracy of pharmacokinetics in humans.
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I) iwasaki.masaru.a6@rdn.daiichisankyo.co.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwasaki
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Chiharu
authors.initials: C
authors.lastname: Katamune
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan (M.I., M.T.); Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan (S.K., C.K., N.M., S.O.); and Translational Medicine and Clinical Pharmacology Department (N.S.) and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan (N.W., T.I).
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D057906:Circadian Clocks; D002940:Circadian Rhythm; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics; D005047:Etoposide / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008252:Macaca fascicularis / Q000033:anatomy & histology / Q000502:physiology*; D008297:Male; D011802:Quinidine / Q000493:pharmacokinetics; D013493:Suprachiasmatic Nucleus / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D056925:Circadian Rhythm Signaling Peptides and Proteins; D000082:Acetaminophen; D005047:Etoposide; D011802:Quinidine