digoxin and talinolol

Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic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

Intestinal P-glycoprotein (P-gp, ABCB1) may significantly influence drug absorption and elimination. Its expression and function is highly variable, regio-selective and influenced by genetic polymorphisms, drug interactions and intestinal diseases. An in vivo probe drug for intestinal P-gp should a registered, safe and well tolerated nonmetabolized selective substrate with low protein binding for which P-gp is rate-limiting during absorption. Other P-gp dependent processes should be of minor influence. The mechanism(s) and kinetics of intestinal uptake must be identified and quantified. Moreover, the release properties of the dosage form should be known. So far, the cardiac glycoside digoxin and the ß₁-selective blocker talinolol have been used in mechanistic clinical studies, because they meet most of these criteria. Digoxin and talinolol are suitable in vivo probe drugs for intestinal P-gp under the precondition, that they are used as tools in carefully designed pharmacokinetic studies with adequate biometrically planning of the sample size and that several limitations are considered in interpreting and discussion of the study results.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Digoxin; Humans; Intestinal Mucosa; Molecular Probe Techniques; Molecular Probes; Propanolamines; Reproducibility of Results

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

Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein.. Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively.. Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration.. We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Adult; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cardiotonic Agents; Chromatography, High Pressure Liquid; Cross-Over Studies; Digoxin; Drug Therapy, Combination; Female; Fluorescence Polarization Immunoassay; Half-Life; Humans; Infusions, Intravenous; Intestinal Absorption; Male; Propanolamines; Reference Values; Time Factors

Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to quantitatively describe drug disposition profiles in vivo, thereby providing an alternative to predict drug-drug interactions (DDIs) that have not been tested clinically. This study aimed to predict effects of rifampin-mediated intestinal P-glycoprotein (Pgp) induction on pharmacokinetics of Pgp substrates via PBPK modeling. First, we selected four Pgp substrates (digoxin, talinolol, quinidine, and dabigatran etexilate) to derive in vitro to in vivo scaling factors for intestinal Pgp kinetics. Assuming unbound Michaelis-Menten constant (K

Topics: Administration, Oral; ATP Binding Cassette Transporter, Subfamily B, Member 1; Dabigatran; Digoxin; Drug Interactions; Female; Gene Expression Regulation; Healthy Volunteers; Humans; Intestinal Mucosa; Male; Models, Biological; Propanolamines; Quinidine; Rifampin

An increase in the area under the curve (AUC) after oral digoxin due to coadministration of drugs known as P-glycoprotein (P-gp) inhibitors has been reported in several studies, but there is very little information on the rate of absorption after P-gp inhibition. Based on an inverse Gaussian density absorption model and using a population approach, the authors reanalyzed data showing an increase in oral digoxin AUC in healthy volunteers after coadministration of talinolol. The model fitted the data well, and the results revealed that the maximum rate of digoxin absorption increased nearly 2-fold, whereas bioavailability increased only by 21%. It is concluded that the increase in the rate of absorption seems to be a better indicator of intestinal P-gp inhibition than the increase in extent of absorption. Furthermore, the authors use a simulation study to demonstrate the ability of the method to estimate bioavailability based on the population characteristics of digoxin disposition kinetics obtained from a different group of healthy volunteers.

Topics: Absorption; Anti-Arrhythmia Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cardiotonic Agents; Computer Simulation; Digoxin; Drug Interactions; Humans; Models, Biological; Normal Distribution; Propanolamines

In the present study we have developed a simple, time, and cost effective in vivo rodent protocol to screen the susceptibility of a test compound for P-glycoprotein (P-gp) mediated efflux at the blood brain barrier (BBB) during early drug discovery. We used known P-gp substrates as test compounds (quinidine, digoxin, and talinolol) and elacridar (GF120918) as a chemical inhibitor to establish the model. The studies were carried out in both mice and rats. Elacridar was dosed intravenously at 5 mg/kg, 0.5 h prior to probe substrate administration. Plasma and brain samples were collected and analyzed using UPLC-MS/MS. In the presence of elacridar, the ratio of brain to plasma area under the curve (B/P) in mouse increased 2, 4, and 38-fold, respectively, for talinolol, digoxin, and quinidine; whereas in rat, a 70-fold increase was observed for quinidine. Atenolol, a non P-gp substrate, exhibited poor brain penetration in the presence or absence of elacridar in both species (B/P ratio ~ 0.1). Elacridar had no significant effect on the systemic clearance of digoxin or quinidine; however, a trend towards increasing volume of distribution and half life was observed. Our results support the utility of elacridar in evaluation of the influence of P-gp mediated efflux on drug distribution to the brain. Our protocol employing a single intravenous dose of elacridar and test compound provides a cost effective alternative to expensive P-gp knockout mice models during early drug discovery.

Topics: Acridines; Animals; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Brain; Chromatography, Liquid; Cost-Benefit Analysis; Digoxin; Drug Design; Drug Interactions; Half-Life; Injections, Intravenous; Male; Mice; Propanolamines; Quinidine; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tetrahydroisoquinolines; Time Factors; Tissue Distribution

Topics: Administration, Oral; Adrenergic beta-Antagonists; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cardiotonic Agents; Digoxin; Drug Interactions; Humans; Intestinal Absorption; Intestinal Mucosa; Propanolamines