RT Journal Article
SR Electronic
T1 Circadian Modulation in the Intestinal Absorption of P-glycoprotein Substrates in Monkeys
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.096735
DO 10.1124/mol.114.096735
A1 Masaru Iwasaki
A1 Satoru Koyanagi
A1 Norio Suzuki
A1 Chiharu Katamune
A1 Naoya Matsunaga
A1 Nobuaki Watanabe
A1 Masayuki Takahashi
A1 Takashi Izumi
A1 Shigehiro Ohdo
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/04/21/mol.114.096735.abstract
AB Recent studies in laboratory rodents have revealed that circadian oscillation in the physiological functions affecting drug disposition underlies the dosing time dependent change in the pharmacokinetics. However, it is difficult to predict the circadian change in the drug pharmacokinetics in diurnal human by using the data collected from nocturnal rodents. In this study, we used cynomolgus monkeys, a diurnal active animal, 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 (SCN; the mammalian circadian pacemaker) of cynomolgus monkeys were similar to those reported in nocturnal rodents. On the other hand, the mRNA expression of circadian clock genes and pharmacokinetic-related factors in the intestinal epithelial cells of monkeys oscillated at opposite phases in rodents. The oscillation in the intestinal expression of P-gp in monkeys was delayed by approximately 12 h relative to its mRNA rhythm. 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.