Mdr1 - cynomolgus monkey

Human MDR1 (ABCB1), more commonly referred to as P-glycoprotein or P-gp, limits the absoption of its substrates in the small intestine, and restricts their distribution into the brain, testes, and placenta [1]. It also eliminates its substrates via biliary and renal excretion. The role of MDR1 in influencing the tissue distribution of drugs is well established, particularly with respect to central nervous system (CNS) exposure [2]. Since MDR1 modulates the bioavailability of some widely prescribed drugs, most notably of digoxin, and MDR1 mediated drug-drug interactions are widely known [1], investigation of experimental drugs for MDR1-mediated DDI is recommended by both EU and US regulatory agencies [3].
While most preclinical DDI studies employ rodents, species differences in the tissue localization, expression levels, and substrate/inhibitor specificities of MDR1 and its animal orthologs are well-documented [4]. In particular, it has been suggested that significant species differences exist between rodents and primates in the drug permeability of the blood-brain barrier [5]. The cynomolgus monkey (Macaca fascicularis) as a nonhuman primate is generally considered a superior model of human drug disposition, and has thus become the most important close-to-human preclinical species in drug development.
However, despite the close evolutionary kinship, human MDR1 (hMDR1) and cynomolgus monkey Mdr1 (cyMdr1) also differ in multiple aspects. Hepatic cyMdr1 expression appears to respond more sensitively to prototypical microsomal inducers such as rifampicin [6], and the baseline mRNA expression of cyMdr1 in the small intestine is significantly higher in cynomolgus monkeys than in humans, which correlates with lower oral absorption of the P-gp substrate drug furosemide [7]. Transporter-related effects may be further obscured by differences in metabolism, such as the more rapid Cyp3a4-mediated degradation of aliskiren in monkey compared to human liver and intestine [8].
A comparison of the in vitro behavior of hMDR1 and cyMdr1 in respect with a specific test drug may facilitate the interpretation of divergences between preclinical and clinical results.


References


1.     Konig, J., F. Muller, and M.F. Fromm, Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev, 2013. 65(3): p. 944-66.
2.     Borst, P. and A.H. Schinkel, P-glycoprotein ABCB1: a major player in drug handling by mammals. J Clin Invest, 2013. 123(10): p. 4131-3.
3.     Maeda, K. and Y. Sugiyama, Transporter biology in drug approval: regulatory aspects. Mol Aspects Med, 2013. 34(2-3): p. 711-8.
4.     Chu, X., K. Bleasby, and R. Evers, Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol, 2013. 9(3): p. 237-52.
5.     Syvanen, S., et al., Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos, 2009. 37(3): p. 635-43.
6.     Nishimura, M., et al., Comparison of inducibility of multidrug resistance (MDR)1, multidrug resistance-associated protein (MRP)1, and MRP2 mRNAs by prototypical microsomal enzyme inducers in primary cultures of human and cynomolgus monkey hepatocytes. Biol Pharm Bull, 2008. 31(11): p. 2068-72.
7.     Takahashi, M., et al., Characterization of gastrointestinal drug absorption in cynomolgus monkeys. Mol Pharm, 2008. 5(2): p. 340-8.
8.     Tsukimoto, M., et al., Effects of the inhibition of intestinal P-glycoprotein on aliskiren pharmacokinetics in cynomolgus monkeys. Biopharm Drug Dispos, 2015. 36(1): p. 15-33.

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