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Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S-fexofenadine
Myers, Michael J.1; Martinez, Marilyn2; Li, Fei1,4; Howard, Karyn1; Yancy, Haile F.1; Troutman, Lisa3; Sharkey, Michele3
2018-12-01
发表期刊JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS
ISSN0140-7783
卷号41页码:805-814
摘要Thirty-two Collies were used to determine the impact of ABCB1 genotype and phenotype on the plasma pharmacokinetics of fexofenadine's (Fex) R- and S-enantiomers after bolus Fex administration, as human P-gp exhibits stereoselectivity. Each Collie's ABCB1 genotype and ivermectin (IVM) sensitivity (phenotype) was determined prior to study enrolment. Wild-type (WT) Collies had lower plasma concentrations of the individual enantiomers as compared to heterozygous IVM nonsensitive (HNS), heterozygous IVM-sensitive (HS) and homozygous mutant (MUT) Collies. Based on pairwise statistical comparison, WT Collies had statistically significantly lower (AUC(0-last)) and peak (C-max) values compared to HS, HNS and MUT Collies. T-max was not influenced by genotype/phenotype. Inter-individual variability in PK metrics tended to be largest for WT Collies. Although the influence of genotype/phenotype on Fex PK occurred with the individual isomers, impairment of S-Fex absorption, particularly in the MUT dogs, exceeded that associated with R-Fex. Since Fex elimination occurs primarily via biliary excretion via a transporter other than P-glycoprotein, and based upon our understanding of Fex absorption kinetics, we attributed these differences primarily to the absorption portion of the profile. These differences are expressed in a stereo-specific manner. These results demonstrate the potential negative impact on estimates of drug effectiveness and toxicity, especially for P-gp substrates that do not exhibit Central Nervous System toxicities.
关键词Collies enantiomers fexofenadine P-glycoprotein
收录类别SCI
语种英语
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/63279
专题中国科学院昆明植物研究所
通讯作者Myers, Michael J.
作者单位1.US FDA, Off Res, Div Appl Vet Res, Ctr Vet Med, 8401 Muirkirk Rd, Laurel, MD 20708 USA
2.US FDA, Off New Anim Drug Evaluat, Ctr Vet Med, Rockville, MD 20857 USA
3.US FDA, Off New Anim Drug Evaluat, Div Therapeut Drugs Nonfood Anim, Ctr Vet Med, Rockville, MD 20857 USA
4.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China
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GB/T 7714
Myers, Michael J.,Martinez, Marilyn,Li, Fei,et al. Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S-fexofenadine[J]. JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS,2018,41(6):805-814.
APA Myers, Michael J..,Martinez, Marilyn.,Li, Fei.,Howard, Karyn.,Yancy, Haile F..,...&Sharkey, Michele.(2018).Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S-fexofenadine.JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS,41(6),805-814.
MLA Myers, Michael J.,et al."Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S-fexofenadine".JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS 41.6(2018):805-814.
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