Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers

Li, Fēi; Howard, Karyn D.; Myers, Michael J.

doi:10.1111/jphp.12687

Cited by 13 publications

(9 citation statements)

References 36 publications

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“…Animal studies have revealed that ABCB1-deficient mice had a five- and nine-time increase in its levels in the plasma and brain [ 54 ]. Moreover, ABCB1 preferentially transports (S)-fexofenadine over (R)-fexofenadine according to studies with canine models [ 55 ]. However, human studies have yielded varied results.…”

Section: Systemic Agentsmentioning

confidence: 99%

ABCB1 in dermatology: roles in skin diseases and their treatment

Weng

Tsai

2021

J Mol Med

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Adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1), also known as permeability glycoprotein, multidrug-resistant protein 1, or cluster of differentiation 243 (CD243), is a crucial protein for purging foreign substances from cells. The functions of ABCB1 have been investigated extensively for their roles in cancer, stem cells, and drug resistance. Abundant pharmacogenetic studies have been conducted on ABCB1 and its association with treatment responsiveness to various agents, particularly chemotherapeutic and immunomodulatory agents. However, its functions in the skin and implications on dermatotherapeutics are far less reported. In this article, we reviewed the roles of ABCB1 in dermatology. ABCB1 is expressed in the skin and its appendages during drug delivery and transport. It is associated with treatment responsiveness to various agents, including topical steroids, methotrexate, cyclosporine, azathioprine, antihistamines, antifungal agents, colchicine, tacrolimus, ivermectin, tetracycline, retinoid acids, and biologic agents. Moreover, genetic variation in ABCB1 is associated with the pathogenesis of several dermatoses, including psoriasis, atopic dermatitis, melanoma, bullous pemphigoid, Behçet disease, and lichen planus. Further investigation is warranted to elucidate the roles of ABCB1 in dermatology and the possibility of enhancing therapeutic efficacy through ABCB1 manipulation.

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Section: Systemic Agentsmentioning

confidence: 99%

ABCB1 in dermatology: roles in skin diseases and their treatment

Weng

Tsai

2021

J Mol Med

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“…Concentration of the R‐ and S‐Fex enantiomers was determined as previously published (Li et al., ) following FDA's Bioanalytical Method Validation GFI (Anonymous, ). Briefly, plasma aliquots (500 μl) were spiked with diphenhydramine as an internal standard, and extracted with acetonitrile.…”

Section: Methodsmentioning

confidence: 99%

“…The second phase examined the impact of TYPE on stereoselectivity, using fexofenadine to address the issue of R‐Fex and S‐Fex concentrations given as a single oral dose of the marketed suspension and evaluated as a function of canine Type. Due to the technical complexity of the stereo‐specific analytical method used in this study, a description of the methods developed has been recently published (Li, Howard, & Myers, ). As a proof of concept, the 0.5 hr and 1.0 hr S‐Fex and R‐Fex concentrations were analysed for 3 WT and 3 MUT dogs.…”

Section: Introductionmentioning

confidence: 99%

Impact ofABCB1 genotype in Collies on the pharmacokinetics of R‐ and S‐fexofenadine

Myers

Martinez

et al. 2018

Vet Pharm & Therapeutics

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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 ) and peak (C ) values compared to HS, HNS and MUT Collies. T 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.

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“…The higher plasma concentrations of ( R )-(+)-fexofenadine are due to the fact that there are multiple transporters capable of chiral discrimination of enantiomers. [ 20 ]. A more recent study demonstrated enantioselectivity in assays to assess the permeability of illicit psychoactive drugs methylone and pentedrone (both derived from cathinone) in Caco-2 cells; ( R )-(-)-pentedrone showed greater permeability and ( S )-(-)-methylone was the most absorbed enantiomer [ 21 ].…”

Section: Enantioselectivity In Drug Pharmacokineticsmentioning

confidence: 99%

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

et al. 2021

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Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

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Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers

Abstract: The information derived from this drug model will be used to determine whether additional safety or efficacy requirements are necessary for enantiomeric drugs that would be used in dogs or humans.

Cited by 13 publications

References 36 publications

ABCB1 in dermatology: roles in skin diseases and their treatment

ABCB1 in dermatology: roles in skin diseases and their treatment

Impact ofABCB1 genotype in Collies on the pharmacokinetics of R‐ and S‐fexofenadine

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

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