2015
DOI: 10.1002/bdd.1991
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Similar substrate specificity of cynomolgus monkey cytochrome P450 2C19 to reported human P450 2C counterpart enzymes by evaluation of 89 drug clearances

Abstract: Cynomolgus monkeys are used widely in preclinical studies as non-human primate species. The amino acid sequence of cynomolgus monkey cytochrome P450 (P450 or CYP) 2C19 is reportedly highly correlated to that of human CYP2C19 (92%) and CYP2C9 (93%). In the present study, 89 commercially available compounds were screened to find potential substrates for cynomolgus monkey CYP2C19. Of 89 drugs, 34 were metabolically depleted by cynomolgus monkey CYP2C19 with relatively high rates. Among them, 30 compounds have bee… Show more

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Cited by 8 publications
(8 citation statements)
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References 27 publications
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“…Loratadine, cleared to 78.9% at a substrate concentration of 1.0 μ m , yielded an almost apparent borderline level of 0.28 nmol/min per nmol CYP2C8. It was already confirmed that amodiaquine and montelukast were hardly depleted by other monkey CYP2C enzymes, CYP2C9, CYP2C19 and CYP2C76 (˂ 0.27 nmol/min per nmol P450) under similar experimental conditions. Therefore, these drugs could be selective marker substrates of monkey CYP2C8.…”
Section: Resultssupporting
confidence: 56%
See 1 more Smart Citation
“…Loratadine, cleared to 78.9% at a substrate concentration of 1.0 μ m , yielded an almost apparent borderline level of 0.28 nmol/min per nmol CYP2C8. It was already confirmed that amodiaquine and montelukast were hardly depleted by other monkey CYP2C enzymes, CYP2C9, CYP2C19 and CYP2C76 (˂ 0.27 nmol/min per nmol P450) under similar experimental conditions. Therefore, these drugs could be selective marker substrates of monkey CYP2C8.…”
Section: Resultssupporting
confidence: 56%
“…In conclusion, the four monkey CYP2C8 substrates identified under the present conditions were all substrates and/or competitive inhibitors of human CYP2C8, indicating that monkey CYP2C8 most likely has similar substrate specificity to human CYP2C8 with slightly different characteristics. Among the newly identified substrates, amodiaquine and montelukast showed high selectivity to CYP2C8 among monkey CYP2C enzymes tested , and could possibly be selective marker substrate candidates of monkey CYP2C8. Our findings on substrate specificity of monkey CYP2C8, in combination with those of monkey CYP2C9, CYP2C19 and CYP2C76, should help to understand more about species differences in drug metabolism between monkeys and humans and to extrapolate the preclinical study data obtained using monkeys to humans.…”
Section: Resultsmentioning
confidence: 98%
“…On the other hand, cynomolgus monkey P450 2C76, which has no ortholog in humans, shows lower amino acid sequence identity to any human P450 2C forms [12]. Because a broad evaluation of potential substrates for cynomolgus monkey P450 2C enzymes was not conducted, to obtain the comprehensive information of substrate selectivity for major cynomolgus monkey P450 2C enzymes, 89 commercially available drugs were investigated [13][14][15][16]. Cynomolgus monkey P450 2C19 metabolized 34 of the 89 compounds, including representative human P450 2C19 substrates such as diazepam and omeprazole and human P450 2C9 substrates such as diclofenac, warfarin, and flurbiprofen [15].…”
mentioning
confidence: 99%
“…Because a broad evaluation of potential substrates for cynomolgus monkey P450 2C enzymes was not conducted, to obtain the comprehensive information of substrate selectivity for major cynomolgus monkey P450 2C enzymes, 89 commercially available drugs were investigated [13][14][15][16]. Cynomolgus monkey P450 2C19 metabolized 34 of the 89 compounds, including representative human P450 2C19 substrates such as diazepam and omeprazole and human P450 2C9 substrates such as diclofenac, warfarin, and flurbiprofen [15]. Cynomolgus monkey P450 2C9 metabolized 20 of the 89 compounds, and 17 of those 20 drugs have been reported as substrates or inhibitors of human P450 2C9 and P450 2C19, but also metabolized efavirenz which is a marker substrate for P450 2B6 in humans [13].…”
mentioning
confidence: 99%
“…Recent studies proposed a mixed origin of Mauritian animals with Indonesian and Indochinese lineage (Blancher et al, 2006;Tosi & Coke, 2007), which could explain this discrepancy. Cynomolgus CYP2C19 is an important enzyme, involved in the metabolism of various human CYP2C substrates (Hosaka et al, 2015;Hosoi et al, 2012;Uno et al, 2006Uno et al, , 2011. Moreover, the CYP2C19 variant substantially influences the enzyme activity toward warfarin (Uno, Matsushita, Shukuya, et al, 2014;Utoh et al, 2015), and thus important for drug metabolism studies.…”
mentioning
confidence: 99%