digoxin and fexofenadine

Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs.. Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies.. Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 Enzyme System; Dabigatran; Digoxin; Drug Interactions; Humans; Propanolamines; Terfenadine

Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Digoxin; Drug Interactions; Genotype; Humans; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Prescription Drugs; Propanolamines; Quinidine; Reproducibility of Results; Terfenadine

Topics: Animals; Antipyrine; Atenolol; Carbamazepine; Cell Membrane; Digoxin; Diltiazem; Diphenhydramine; Drug Elimination Routes; Gabapentin; Lamotrigine; Liver; Memantine; Membrane Transport Proteins; Microdialysis; Muscle, Skeletal; Ofloxacin; Pharmaceutical Preparations; Propranolol; Pyrilamine; Quinidine; Rats; Terfenadine

P-glycoprotein (P-gp) is an ATP-dependent efflux transporter highly expressed in gastrointestinal tract and multidrug resistance tumor cells. Inhibition or induction of P-gp can cause drug-drug interactions and thus influence the effects of P-gp substrate drugs. Previous studies indicated that 20(S)-ginsenoside Rh2 [20(S)-Rh2] could synergistically enhance the anticancer effects of conventional chemotherapeutic agents at a nontoxic dose. The aim of present study was to investigate in vitro and in vivo whether 20(S)-Rh2 was a P-gp inhibitor and analyze the possible inhibitory mechanisms and potential herb-drug interactions. Results showed that in vitro, 20(S)-Rh2 significantly enhanced rhodamine 123 retention in cells and decreased the efflux ratio of digoxin, fexofenadine, and etoposide, which were comparable to the effects of the established P-gp inhibitor verapamil. However, the transport of 20(S)-Rh2 suggested that 20(S)-Rh2 was not a P-gp substrate. Furthermore, the inhibitory effect persisted for at least 3 h after removal of 20(S)-Rh2. Unlike P-gp substrates, 20(S)-Rh2 inhibited both basal and verapamil-stimulated P-gp ATPase activities. It also significantly decreased UIC2 binding fluorescence, a marker for conformational change of P-gp. In situ and in vivo experiments showed that 20(S)-Rh2 increased the area under the plasma concentration-time curve and maximum plasma concentration of digoxin, fexofenadine, and etoposide significantly without affecting terminal elimination half-time. Long-term treatment with 20(S)-Rh2 failed to affect intestinal P-gp expression in vitro and in vivo. In conclusion, 20(S)-Rh2 is a potent noncompetitive P-gp inhibitor, which indicates a potential herb-drug interaction when 20(S)-Rh2 is coadministered with P-gp substrate drugs. It could increase the absorption of P-gp substrate drugs without long-term induction of P-gp expression in rats.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Digoxin; Etoposide; Ginsenosides; Herb-Drug Interactions; Humans; Ileum; Male; Rats; Rats, Sprague-Dawley; Rhodamine 123; Terfenadine; Verapamil

Effects of coadministration of dietary supplement biochanin A (BA) on the pharmacokinetics of three P-glycoprotein substrates, paclitaxel, digoxin, and fexofenadine, were investigated in rats. With BA coadministration, the oral bioavailability and peak plasma concentration were markedly increased by 3.77- and 2.04-fold for paclitaxel, 1.75- and 1.71-fold for digoxin, but were reduced by 0.694- and 0.429-fold for fexofenadine, respectively. Paclitaxel is a Pgp and CYP3A substrate, the drastic increase in systemic exposure may be attributed to the synergistic inhibition of Pgp and CYP3A by BA in the intestine. Digoxin is a substrate for Pgp, CYP3A, and Oatp2. BA may suboptimally inhibit Pgp and CYP3A, resulting in a moderate increase in oral bioavailability of digoxin. Fexofenadine is a substrate for Pgp, Oatp1, Oatp2, and Oatp3. BA appears to preferentially inhibit Oatp3 over Pgp in the intestine, leading to the decreased oral absorption of fexofenadine. No significant changes in mean residence time and terminal half-life were observed for all drugs, suggesting a negligible effect of BA on their hepatic/renal elimination. These findings demonstrate the importance of interplay among uptake/efflux transporters and metabolizing enzymes. The enhanced oral absorption by BA coadministration may be exploited to improve oral bioavailability of Pgp and CYP3A substrate compounds.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cardiotonic Agents; Chromatography, Liquid; Digoxin; Genistein; Half-Life; Histamine H1 Antagonists; Injections, Intravenous; Male; Mass Spectrometry; Paclitaxel; Rats; Rats, Sprague-Dawley; Terfenadine

P-glycoprotein (P-gp) and organic anion transporting polypeptides (Oatp) are expressed at the blood-brain barrier (BBB). There is little functional evidence for Oatp-mediated transport at the BBB. The peptidic delta opioid-receptor agonist [D-penicillamine(2,5)]-enkephalin (DPDPE) is a substrate of mdr1a P-gp and Oatp2. The present study evaluated the influence of these transporters on brain uptake of DPDPE by in situ perfusion in mice. Brain uptake was increased approximately 12-fold in mice lacking P-gp in the BBB, but the P-gp inhibitor dexverapamil did not increase uptake in P-gp-competent mice. In P-gp-deficient mice, DPDPE uptake was saturable (K(m) approximately 24 mM), and was inhibited by dexverapamil and the Oatp2 substrates digoxin, estradiol-17beta-glucuronide and fexofenadine. These results confirm P-gp-mediated efflux of DPDPE, and suggest functional uptake transport of DPDPE by Oatp, at the murine BBB.

Topics: Analgesics, Opioid; Animals; Anion Transport Proteins; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Blood-Brain Barrier; Calcium Channel Blockers; Carrier Proteins; Digoxin; Enkephalin, D-Penicillamine (2,5)-; Enzyme Inhibitors; Estradiol; Histamine H1 Antagonists; Male; Mice; Mice, Knockout; Perfusion; Receptors, Opioid, delta; Terfenadine; Verapamil

MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.

Topics: Africa; Alleles; Anti-Allergic Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Black People; Cloning, Molecular; Digoxin; DNA Primers; Enzyme Inhibitors; Europe; Genes, MDR; Genetic Variation; Genotype; Haplotypes; Humans; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Terfenadine; Time Factors; White People