CYP2C19 polymorphisms account for inter-individual variability of drug metabolism in cynomolgus macaques

Uno, Yasuhiro; Matsushita, Akinori; Shukuya, Mitsunori; Matsumoto, Y.; Murayama, Norie; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2014.07.004

Cited by 31 publications

(45 citation statements)

References 20 publications

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“…Although genetic variants in human and macaque P450 2C genes account for the interindividual variability in drug oxidation activities (Uno et al, 2014a;Utoh et al, 2015), genetic variants have not yet been investigated in marmoset P450 2C19. The pharmacokinetics of the human P450 probes caffeine, warfarin, omeprazole, metoprolol, and midazolam (Turpault et al, 2009) were investigated in mice transplanted with human hepatocytes, marmosets, monkeys, dogs, and minipigs at doses of 1.0 mg/kg to clarify the similarities and occasional species differences (Mogi et al, 2012;Koyanagi et al, 2015;Uehara et al, 2016;Utoh et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…The Old World Monkeys such as cynomolgus monkeys (Macaca fascicularis) are the most frequently used among the nonhuman primate species. Cynomolgus monkey P450 2C9 (Uno et al, 2015a), 2C19 (Uno et al, 2014a;Utoh et al, 2015), 2C76 (Uno et al, 2009), and 2D6 (Uno et al, 2014b(Uno et al, , 2015b are polymorphic in drug metabolism, similar to human P450s. Furthermore, development of a genotyping tool for a functionally relevant P450 2C19 allele p. [(Phe100Asn;Ala103Val;Ile112Leu)] in cynomolgus macaques was recently reported (Uno et al, 2014a;Uno and Yamazaki, 2016).…”

Section: Introductionmentioning

confidence: 91%

“…Cynomolgus monkey P450 2C9 (Uno et al, 2015a), 2C19 (Uno et al, 2014a;Utoh et al, 2015), 2C76 (Uno et al, 2009), and 2D6 (Uno et al, 2014b(Uno et al, , 2015b are polymorphic in drug metabolism, similar to human P450s. Furthermore, development of a genotyping tool for a functionally relevant P450 2C19 allele p. [(Phe100Asn;Ala103Val;Ile112Leu)] in cynomolgus macaques was recently reported (Uno et al, 2014a;Uno and Yamazaki, 2016). One of the New World Monkeys, the common marmoset (Callithrix jacchus), is used in various research fields such as drug metabolism because of advantageous features including their small body size (Sasaki, 2015).…”

Section: Introductionmentioning

confidence: 91%

“…Cynomolgus monkey P450 2C19 has high activity toward R-warfarin 7-hydroxylation (Hosoi et al, 2012), whereas marmoset P450 2C19 efficiently catalyzes S-warfarin 7-hydroxylation . Interanimal variations of R-warfarin clearance in cynomolgus monkeys are accounted for by the monkey P450 2C19 genetic variant p.[(Phe100Asn; Ala103Val; Ile112Leu)] (Uno et al, 2014a;Utoh et al, 2015). In addition, the previous study indicated that optical resolution for plasma concentrations of S-warfarin in marmosets rapidly decreased than those of R-warfarin after intravenous administration of racemic warfarin, indicating that S-warfarin is stereoselectively metabolized in marmoset livers, similar to human livers , as mean values.…”

Section: Introductionmentioning

confidence: 94%

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Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Uehara

Uno

Inoue

et al. 2016

Drug Metabolism and Disposition

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Marmoset cytochrome P450 2C19, highly homologous to human P450 2C9 and 2C19, has been identified in common marmosets (Callithrix jacchus), a nonhuman primate species used in drug metabolism studies. Although genetic variants in human and macaque P450 2C genes account for the interindividual variability in drug metabolism, genetic variants have not been investigated in the marmoset P450 2C19. In this study, sequencing of P450 2C19 in 24 marmosets identified three variants p.[(Phe7Leu; Ser254Leu; Ile469Thr)], which showed substantially reduced metabolic capacity of S-warfarin compared with the wild-type group in vivo and in vitro. Although mean plasma concentrations of R-warfarin in marmosets determined after chiral separation were similar between the homozygous mutant and wild-type groups up to 24 hours after the intravenous and oral administrations of racemic warfarin, S-warfarin depletion from plasma was significantly faster in the three wild-type marmosets compared with the three homozygous mutant marmosets. These variants, cosegregating in the marmosets analyzed, influenced metabolic activities in 18 marmoset liver microsomes because the homozygotes and heterozygotes showed significantly reduced catalytic activities in liver microsomes toward S-warfarin 7-hydroxylation compared with the wild-type group. Kinetic analysis for S-warfarin 7-hydroxylation indicated that the recombinant P450 2C19 Ser254Leu variant would change the metabolic capacity. These results indicated that the interindividual variability of P450 2C-dependent drug metabolism such as S-warfarin clearance is at least partly accounted for by P450 2C19 variants in marmosets, suggesting that polymorphic P450 2C-dependent catalytic functions are relatively similar between marmosets and humans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 94%

See 2 more Smart Citations

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Uehara

Uno

Inoue

et al. 2016

Drug Metabolism and Disposition

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“…This is especially so in the area of infectious disease research concerning pathogens such as human immunodeficiency virus type 1 and tuberculosis (Legrand et al, 2009;Holder et al, 2014;Phillips et al, 2014;Scanga and Flynn, 2014), as the host-pathogen interactions involved in these pathologies are most accurately reproduced in a NHP model. In these diseases as well as others, NHP models are often used to test the efficacy of therapeutic agents that are metabolized by the P450 pathway (Nishimuta et al, 2011;Uno et al, 2014). Even though the NHP models can accurately reproduce the pathogenic effects of the pathogen as well as model drug disposition, the use of drugs of abuse must also be taken into account.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Methamphetamine Metabolism in Rhesus Macaque as Compared with Human: An Analysis Using a Novel Method of Liquid Chromatography with Tandem Mass Spectrometry, Kinetic Study, and Substrate Docking

Earla

Kumar²,

Wang

et al. 2014

Drug Metabolism and Disposition

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Methamphetamine (MA), which remains one of the widely used drugs of abuse, is metabolized by the cytochrome P450 (P450) family of enzymes in humans. However, metabolism of methamphetamine in macaques is poorly understood. Therefore, we first developed and validated a very sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method using solid phase extraction of rhesus plasma with a lower limit of quantitation at 1.09 ng/ml for MA and its metabolites, 4-hydroxy methamphetamine (4-OH MA), amphetamine (AM), 4-OH amphetamine (4-OH AM), and norephedrine. We then analyzed plasma samples of MA-treated rhesus, which showed >10-fold higher concentrations of AM (∼29 ng/ml) and 4-OH AM (∼28 ng/ml) than MA (∼2 ng/ml). Because the plasma levels of MA metabolites in rhesus were much higher than in human samples, we examined MA metabolism in human and rhesus microsomes. Interestingly, the results showed that AM and 4-OH AM were formed more rapidly and that the catalytic efficiency (V max /K m ) for the formation of AM was ∼8-fold higher in rhesus than in human microsomes. We further examined the differences in these kinetic characteristics using three selective inhibitors of each human CYP2D6 and CYP3A4 enzymes. The results showed that each of these inhibitors inhibited both D-and L-MA metabolism by 20%-60% in human microsomes but not in rhesus microsomes. The differences between human and rhesus CYP2D6 and CYP3A4 enzymes were further assessed by docking studies for both d and l-MA. In conclusion, our results demonstrated an enhanced MA metabolism in rhesus compared with humans, which is likely to be caused by differences in MA-metabolizing P450 enzymes between these species.

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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

Hosaka

Murayama

Satsukawa

et al. 2015

Biopharm & Drug Disp

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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 been reported as substrates or inhibitors of, either or both, human CYP2C19 and CYP2C9. Several compounds, including loratadine, showed high selectivity to cynomolgus monkey CYP2C19, and all of these have been reported as human CYP2C19 and/or CYP2C9 substrates. In addition, cynomolgus monkey CYP2C19 formed the same loratadine metabolite as human CYP2C19, descarboethoxyloratadine. These results suggest that cynomolgus monkey CYP2C19 is generally similar to human CYP2C19 and CYP2C9 in its substrate recognition functionality.

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CYP2C19 polymorphisms account for inter-individual variability of drug metabolism in cynomolgus macaques

Cited by 31 publications

References 20 publications

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers

Enhanced Methamphetamine Metabolism in Rhesus Macaque as Compared with Human: An Analysis Using a Novel Method of Liquid Chromatography with Tandem Mass Spectrometry, Kinetic Study, and Substrate Docking

Similar substrate specificity of cynomolgus monkey cytochrome P450 2C19 to reported human P450 2C counterpart enzymes by evaluation of 89 drug clearances

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