Lack of Effects of Diltiazem on Digoxin Pharmacokinetics
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Diltiazem is a member of a class of pharmacologic agents that block the passage of calcium ions across cell membranes, the calcium‐channel blockers. Several investigators have reported a clinically important pharmacokinetic and pharmacologic interaction between digoxin and verapamil. 1–4 Despite earlier suggestions of such an interaction with nifedipine, recent works have convincingly shown that no pharmacokinetic changes occur. 5–7 Thus, it appears that nifedipine has no clinically significant interaction with digoxin. Similar work has been limited with diltiazem. A recent investigation by Yoshida and associates, 8 suggested no increase in digoxin serum concentration and a slight decrease in renal digoxin clearance after diltiazem had been added versus a control period. Rameis and co‐workers 9 recently reported a 22.4% increase in serum digoxin concentration when diltiazem was added. The purpose of this study was to further evaluate this potential interaction.Keywords:
Pharmacokinetic interaction
Abstract: Diltiazem, as well as other calcium entry blockers, is widely prescribed for the treatment of various types of angina. This review summarizes the current state of knowledge of the pharmacokinetics of diltiazem and of two other calcium entry blockers: verapamil and nifedipine. Although unrelated in their chemical structure, these three drugs have common features. They are highly lipophilic and have a large volume of distribution, are mainly cleared by metabolism and undergo an extensive first‐pass extraction. On the other hand, as expected from their quite dissimilar structures, they have their own particular kinetic characteristics. For example, metabolism of diltiazem and verapamil gives rise to active metabolites; repeated administration influences the kinetic profile of verapamil but not those of diltiazem and nifedipine. Absorption, distribution and elimination of these three drugs are differently affected by age and pathological conditions. The possible drug interactions involving diltiazem and the other calcium entry blockers are discussed, particularly that with digoxin. Due to its large therapeutic index, there is no need for treatment monitoring of diltiazem. Nevertheless, this procedure may provide useful information for optimizing the dosage regimen of each patient as the pathological condition and drug therapy may be quite complex.
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Pharmacotherapy
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The effects of five calcium antagonists, verapamil, diltiazem, nifedipine, darodipine and isradipine, on rat liver microsomal drug metabolism in vitro and in vivo were studied. All compounds prolonged hexobarbital-induced sleeping time in a dose-dependent manner (doses 3.0 and 30.0 mg/kg, except nifedipine 0.3 and 3.0 mg/kg) and inhibited cytochrome P450-dependent N-demethylation of aminopyrine in vitro in rat liver microsomes. The incubation of all compounds with microsomes resulted in the apparent formation of formaldehyde, suggesting either N- or O-demethylation. Diltiazem, isradipine and darodipine gave rise to a type I spectral change. Nifedipine seemed to produce a type II spectral change. A spectrum of verapamil changed from a type I to a type II as concentration increased. These results indicate that all calcium antagonists studied interact with P450 and are in vitro inhibitors of microsomal drug metabolism in the rat and the inhibition brings out pharmacokinetic drug-drug interactions in vivo.
Isradipine
Hexobarbital
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Active metabolite
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Digoxin and midazolam are routinely used as probe drugs to measure in vivo activity of P-glycoprotein (P-gp) and cytochrome P450 3A4/5 (CYP3A), respectively. We investigated whether digoxin and midazolam could be coadministered to simultaneously determine P-gp and CYP3A activity without a significant pharmacokinetic interaction. In a randomized crossover design, digoxin (0.5 mg oral) or midazolam (2.0 mg oral) was administered individually or in combination (digoxin 1 hour after midazolam) to 14 healthy volunteers. Blood and urine samples were collected for up to 48 hours. Pharmacokinetic parameters of digoxin, midazolam and 1'-OH midazolam were evaluated to determine the presence of an interaction. The geometric mean ratios of all measured pharmacokinetic parameters of digoxin and midazolam were not significantly affected by coadministration. Coadministration of digoxin and midazolam can be used to simultaneously phenotype P-gp and CYP3A activity without a significant pharmacokinetic interaction.
Midazolam
CYP3A
Crossover study
P-glycoprotein
Pharmacokinetic interaction
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Summary: Calcium antagonists are a biochemically heterogeneous group of drugs that share the property of blocking the entry of calcium into cells by voltage-operated channels in cardiac and smooth muscle. They are useful in the management of angina pectoris and hypertension. The drugs available at present include nifedipine, verapamil, and diltiazem. All three drugs have similar pharmacokinetic properties of low and variable bioavailability, high first-pass metabolism, short elimination halflife, and active metabolites. The pharmacokinetics of calcium antagonists are relevant, because in individual patients the intensity and duration of the pharmacological effect is related to the level of drug in plasma. Amlodipine is a new dihydropyridine calcium antagonist in advanced clinical development. It has a completely different pharmacokinetic profile. It is water soluble and photostable, and has a long half-life of 35-50 h. Amlodipine is slowly absorbed, its absolute bioavailability is high, and it is extensively metabolized in the liver. The long half-life is associated with a prolonged (>24 h) duration of pharmacodynamic action. Amlodipine, because of its novel pharmacokinetics, may offer practical advantages over existing calcium antagonists in the long-term treatment of cardiovascular disease.
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Quinidine
Nicardipine
Cimetidine
Bepridil
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Introduction: The potential for ezogabine/retigabine (EZG/RTG) and its N -acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600–1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety. Methods: An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations. Results: Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration–time curve (AUC) 0–120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01–1.15; 1.18, 90% CI 1.10–1.27; 1.13, 90% CI 1.05–1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects. Conclusion: Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary. Keywords: digoxin, retigabine, ezogabine, drug–drug interactions
Therapeutic index
Active metabolite
Tolerability
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Diltiazem is a member of a class of pharmacologic agents that block the passage of calcium ions across cell membranes, the calcium‐channel blockers. Several investigators have reported a clinically important pharmacokinetic and pharmacologic interaction between digoxin and verapamil. 1–4 Despite earlier suggestions of such an interaction with nifedipine, recent works have convincingly shown that no pharmacokinetic changes occur. 5–7 Thus, it appears that nifedipine has no clinically significant interaction with digoxin. Similar work has been limited with diltiazem. A recent investigation by Yoshida and associates, 8 suggested no increase in digoxin serum concentration and a slight decrease in renal digoxin clearance after diltiazem had been added versus a control period. Rameis and co‐workers 9 recently reported a 22.4% increase in serum digoxin concentration when diltiazem was added. The purpose of this study was to further evaluate this potential interaction.
Pharmacokinetic interaction
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