Ciência e Tecnologia Veterinária

Cytochrome P450 2D14 (CYP2D14) Gene Deletion Variants in the Japanese Black Cattle and Characterization of their Effects on Metoclopramide Pharmacokinetics

Abstract

Kouko Hamamoto, Yasuharu Mizuno, Mayumi Kijima, Tsuyoshi Abe, Eiji Kobayashi, Masaki Kato, Norio Yamagishi and Kazuhisa Furuhama

The frequency of cytochrome P450 2D14 (CYP2D14) genetic polymorphisms and their effects on CYP2D14- mediated metabolism have not been reported in cattle. Genetic polymorphisms of the CYP2D14 gene in 57 Japanese Black (JB) cattle were determined by polymerase chain reaction (PCR)-direct sequencing. Two types of CYP2D14 gene deletion variants (GD), GD1 and GD2, were observed in this study. The CYP2D6 deletion reportedly results in delayed metabolism of metoclopramide in human. To investigate the effects of CYP2D14 gene deletion in JB cattle, the GD1, GD2 and wild-type (WT) cattle were administered metoclopramide by an intravenous or oral route. Plasma concentrations of metoclopramide in GD1 cattle were significantly higher 24 hour (h) after intravenous administration (P<0.01) and within 1 h after oral administration of metoclopramide compared to levels in GD2 and WT cattle (P<0.01). The half-life at γ-phase (γHL) of metoclopramide after intravenous administration was significantly higher in GD1 compared to WT cattle (P<0.05). Moreover, the elimination rate constant (K10) of GD1 after oral administration of metoclopramide was significantly higher in GD1 compared to WT animals (P<0.05). These results suggest that the higher plasma concentration of metoclopramide in GD1 cattle is caused by delayed metabolism of metoclopramide, owing to CYP2D14 enzyme deficiency.