Similar substrate specificity of cynomolgus monkey cytochrome P450 2C19 to reported human P450 2C counterpart enzymes by evaluation of 89 drug clearances.
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.
Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.|Kaken Pharmaceutical Co., LTD., Shizuoka, 426-8646, Japan.
Shinya
S
Hosaka
Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
Norie
N
Murayama
Kaken Pharmaceutical Co., LTD., Shizuoka, 426-8646, Japan.
Masahiro
M
Satsukawa
Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
Shotaro
S
Uehara
Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
Makiko
M
Shimizu
Shin Nippon Biomedical Laboratories, Ltd, Kainan, Wakayama, 642-0017, Japan.
Kazuhide
K
Iwasaki
Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.|Novartis Pharma K.K., Tokyo, 106-8618, Japan.
Shunsuke
S
Iwano
Shin Nippon Biomedical Laboratories, Ltd, Kainan, Wakayama, 642-0017, Japan.
Yasuhiro
Y
Uno
Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
Hiroshi
H
Yamazaki
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D017336:Loratadine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008252:Macaca fascicularis / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011994:Recombinant Proteins / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism*
D039563:Histamine H1 Antagonists, Non-Sedating; D007527:Isoenzymes; D011994:Recombinant Proteins; D015262:Xenobiotics; D017336:Loratadine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C121345:desloratadine
CYP2C19 substrates; cynomolgus monkey; loratadine