digoxin and candesartan-cilexetil

The aim of this series of studies was to determine the potential for pharmacokinetic interaction between candesartan (administered orally as the prodrug candesartan cilexetil) and hydrochlorothiazide (HCTZ), nifedipine, glibenclamide, warfarin, digoxin or the components of an oral contraceptive formulation. All studies were performed in healthy volunteers using randomised, crossover or add-on study designs. Candesartan cilexetil was administered orally at doses of 8, 12 or 16 mg. The pharmacokinetic parameters were determined for comparator agents and candesartan following administration of each agent alone or in combination. There were no changes in the drug plasma concentrations of nifedipine, glibenclamide, digoxin or oral contraceptives when co-administered with candesartan cilexetil. Co-administration of candesartan cilexetil caused a slight but significant decrease in the AUC of HCTZ. However, the 90% confidence intervals (CI) for AUC ratios for HCTZ when co-administered with candesartan cilexetil were within the defined limits of bioequivalence. Candesartan cilexetil produced a 7% decrease in trough plasma warfarin concentration but this had no effect on prothrombin time. Co-administration of candesartan cilexetil with HCTZ produced a statistically significant increase in the bioavailability and Cmax values for candesartan (18% and 25%, respectively). However, this increase is not considered to be clinically relevant. No other co-administered drug (nifedipine, glibenclamide, digoxin, oral contraceptive) affected the pharmacokinetic parameters of candesartan. Candesartan cilexetil was well tolerated both alone and in combination with the other agents.

Topics: Adolescent; Adult; Angiotensin Receptor Antagonists; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Digoxin; Drug Interactions; Female; Glyburide; Humans; Hydrochlorothiazide; Male; Middle Aged; Nifedipine; Tetrazoles; Warfarin

The inhibitory effect of angiotensin II type 1 receptor blockers (ARBs) on P-glycoprotein (P-gp) was examined to evaluate their clinical drug-drug interaction (DDI) potential.. We performed an inhibition study on the vectorial transport of digoxin, a typical substrate for P-gp, using a human colonic adenocarcinoma cell line, Caco-2 cells, and verapamil-stimulated ATPase activity using human multidrug resistance 1 (hMDR1)-expressing membrane.. The vectorial transport of digoxin was inhibited by candesartan cilexetil, irbesartan and telmisartan with the IC(50) values of 14.7, 34.0 and 2.19microM, respectively. Those values were 7.4-426-fold higher than their theoretical clinical gastrointestinal concentration [I] at doses in clinical DDI studies. Other ARBs failed to show interaction with P-gp.. It was demonstrated that candesartan cilexetil, irbesartan and telmisartan had the potential to inhibit the transport of various drugs via P-gp. Telmisartan, which caused an increase in the serum digoxin concentration in humans, had a sufficiently high [I]/IC(50) value, suggesting that DDI between digoxin and telmisartan was caused by the inhibition of digoxin efflux via intestinal P-gp.

Topics: Adenosine Triphosphatases; Angiotensin II Type 1 Receptor Blockers; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Benzoates; Biological Transport; Biphenyl Compounds; Caco-2 Cells; Calcium Channel Blockers; Cardiotonic Agents; Cell Membrane; Digoxin; Drug Interactions; Humans; Irbesartan; Losartan; Telmisartan; Tetrazoles; Verapamil

ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Benzimidazoles; Biological Transport; Biphenyl Compounds; Digoxin; Fluoresceins; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Membrane Transport Proteins; Mice; Multidrug Resistance-Associated Protein 2; Olmesartan Medoxomil; Tetrazoles; Thiophenes

trans-1,2-Cyclohexanediol, the major metabolite of the cilexetil moiety of candesartan cilexetil (CC), has been reported to have potent pro-arrhythmic effects in dogs with congestive heart failure (CHF), especially when co-administered with digoxin. To verify this and to clarify the clinical relevance and the underlying mechanisms, a series of in vivo and in vitro experiments was conducted. When CC up to 300 mg/kg was administered orally to intact dogs, no changes in the electrocardiograms (ECG) or the required cumulative doses of ouabain to induce ventricular arrhythmias were observed. In dogs with CHF, intravenous bolus administration of trans-1,2-cyclohexanediol at 4 mg/kg followed by continuous infusion at 0.1 mg x kg(-)(1) x min(-)(1) had no effects on the ECG parameters, the type, incidence, and onset time of digoxin-induced arrhythmias or the metabolism of digoxin. In an in vitro experiment using isolated guinea pig papillary muscle, trans-1,2-cyclohexanediol (1 - 100 micromol/L) showed no effects on any parameter of the action potentials. Because no effects were observed in these experiments where the exposure levels of trans-1,2-cyclohexanediol were extremely high compared to those in humans given the maximum therapeutic dose of CC, it is unlikely that CC would induce arrhythmias in clinical use even in patients treated with cardiac glycosides.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Benzimidazoles; Biphenyl Compounds; Cyclohexanols; Digoxin; Dogs; Drug Interactions; Guinea Pigs; Heart Failure; In Vitro Techniques; Male; Papillary Muscles; Tetrazoles

Potential risks of cyclohexanol (CH) and cyclohexanediol (CHD) isomers, which are the metabolites derived from cilexetil ester side-chain of several prodrugs such as antibiotics (e.g. cefotiam hexetil) and an antihypertensive agent (candesartan cilexetil), were examined in beagles that were made congestive heart failure (CHF) by rapid ventricular pacing. The following three experiments tested the cardiac effects of i.v. doses of: (1) the metabolites alone, (2) the metabolites under the digoxin-induced bradycardia, and (3) the metabolites given concomitantly with digoxin (0.02 mg kg(-1)). Experiment 1: t-1,2- or 1,4-CHD alone (0.1-12 mg kg(-1)) exerted transient yet reproducible supraventricular or ventricular arrhythmia dose-dependently, whereas CH and 1,3-CHD at 12 mg kg(-1) showed no cardiac effect at all. Experiment 2: t-1,2-CHD (0.1-4 mg kg(-1)), but not CH or 1,3-CHD, induced the additive arrhythmia dose-dependently; t-1,2-CHD (12 mg kg(-1)) caused frequent premature supraventricular contractions and/or irreversible paroxysmal supraventricular tachycardia. Experiment 3: t-1,2-CHD, not CH or 1,3-CHD, caused fatal arrhythmia: one dog showed torsade de pointes followed by ventricular fibrillation, while another showed 3rd degree atrioventricular block and eventually cardiac arrest. In both Experiments 2 and 3, saline vehicle added onto digoxin never caused the irreversible, fatal arrhythmia. In a separate study using healthy dogs without CHF, none of these metabolites did produce cardiac effect. Given the potential risk of generating cardiotoxic metabolites from cilexetil-bearing prodrugs, the use of such prodrugs should be avoided from the patients with CHF, particularly from those who are receiving cardiac glycosides.

Topics: Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Benzimidazoles; Biphenyl Compounds; Cardiac Pacing, Artificial; Cardiotonic Agents; Digoxin; Dogs; Dose-Response Relationship, Drug; Heart Failure; Heart Ventricles; Prodrugs; Tetrazoles