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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
Source PublicationJOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS
ISSN0140-7783
Volume41Issue:6Pages:805-814
AbstractThirty-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.
KeywordCollies enantiomers fexofenadine P-glycoprotein
Indexed BySCI
Language英语
WOS IDWOS:000451777000004
Citation statistics
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/63279
Collection中国科学院昆明植物研究所
Corresponding AuthorMyers, Michael J.
Affiliation1.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
Recommended Citation
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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