The pharmacokinetics of diltiazem in healthy American men

doi:10.1016/S0002-9149(82)80007-6

The American Journal of Cardiology

Volume 49, Issue 3, 1982, Pages 529-532

https://doi.org/10.1016/S0002-9149(82)80007-6 Get rights and content

Plasma diltiazem concentration was determined for 24 hours after oral administration of 30, 60, 90 and 120 mg (sustained release tablets) in healthy adult white men. The plasma concentration was too low after the 30 mg dose to calculate pharmacokinetic variables. After administration of 60 mg (n = 12), 90 mg (n = 10), and 120 mg (n = 4), peak plasma concentrations were 72, 117, and 152 ng/cm³ and time to peak concentrations were 3.9, 3.3, and 4.0 hours, respectively. Half-lives for clearance from the plasma were 4.1, 5.1, and 5.6 hours and areas under the concentration-time curve were 514, 984, and 1258 ng/hour per cc, respectively. There was wide variability among patients after the administration of a single dose. The area under the curve also tended to increase more than the multiple of the dose administered.

If the plasma diltiazem concentration is quantitatively related to efficacy and toxicity, then these data suggest that dosage requirements may vary considerably from patient to patient. Therefore, if a patient fails to respond sufficiently, the plasma drug concentration should be determined to see if adequate concentration has been attained. Alternatively, if the drug should prove to have a high therapeutic index, one might simply administer more than the usually required dose of diltiazem.

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Polypharmacy is a common issue, especially among elderly patients resulting in administration errors and patient inconvenience. Hypertension is a prevalent health condition that frequently leads to polypharmacy, as its treatment typically requires the co-administration of more than one different Active Pharmaceutical Ingredients (API’s). To address these issues, floating hollow torus-shaped dosage forms were developed, aiming at providing prolonged gastric retention and sustained drug release. The dosage forms (polypills) containing three anti-hypertensive API’s (diltiazem (DIL), propranolol (PRP) and hydrochlorothiazide (HCTZ)) were created via Fused Deposition Modelling 3D printing. A multitude of the dosage forms were loaded into a capsule and the resulting formulation achieved prolonged retention times over a 12-hour period in vitro, by leveraging both the buoyancy of the dosage forms, and the “cheerios effect” that facilitates the aggregation and retention of the dosage forms via a combination of surface tension and shape of the objects. Physicochemical characterization methods and imaging techniques were employed to investigate the properties and the internal and external structure of the dosage forms. Furthermore, an ex vivo porcine stomach model revealed substantial aggregation, adhesion and retention of the 3D printed dosage forms in porcine stomach. In vitro dissolution testing demonstrated almost complete first-order release of PRP and DIL (93.52 % and 99.9 %, respectively) and partial release of HCTZ (65.22 %) in the 12 h timeframe. Finally, a convolution-based single-stage approach was employed in order to predict the pharmacokinetic (PK) parameters of the API’s of the formulation and the resemblance of their PK behavior with previously reported data.
A novel micellar per aqueous liquid chromatographic method for simultaneous determination of diltiazem hydrochloride, metoprolol tartrate and isosorbide mononitrate in human serum
2014, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Citation Excerpt :
In fact, because of the difference of individual resistant ability and the great variation of individual conditions, the dosage of these drugs should be adjusted appropriately by the routine observation of clinical symptoms. For diltiazem hydrochloride (DI), the dosage requirements may vary considerably from patient to patient, if a patient fails to respond sufficiently, the plasma drug concentration should be determined to see if the adequate concentration has been attained [3]. For metoprolol tartrate (ME), the individual variation of the serum concentration is great.
A novel micellar per aqueous liquid chromatographic method was investigated to simultaneously determine diltiazem hydrochloride, metoprolol tartrate and isosorbide mononitrate in human serum. Separation and determination of the analytes were performed on a Pinnacle II Cyano column as the stationary phase using the mobile phase consisted of aqueous solution (4.15 × 10⁻² mol/L sodium dodecyl sulfate and 0.02 mol/L sodium dihydrogen phosphate) with 10% (v/v) of 1-propanol at pH 7.0. This method was validated by linearity, lower limit of quantification, extraction recovery, stability, precision, and accuracy. The main analytical parameters were linearity (r > 0.9950), intra- and inter-day precisions (intra-day RSD 2.2–3.5%, and inter-day RSD 3.7–9.5%), lower limit of quantification (20 ng mL⁻¹ for isosorbide mononitrate, metoprolol tartrate and diltiazem hydrochloride). The extraction recovery was 63.3% (0.1 μg/mL), 65.6% (1.0 μg/mL), and 69.5% (25 μg/mL) for isosorbide mononitrate; 65.1% (0.1 μg/mL), 69.5% (1.0 μgmL) and 73.5% (2.5 μg/mL) for metoprolol tartrate; 67 .1% (0.1 μg/mL), 68.8% (1.0 μg/mL) and 73.8 % (2.5 μg/mL) for diltiazem hydrochloride. The relative error of stability was <6.4% at the room temperature for 24 h, <3.8% at 4 °C for 1 week, <4.6% at −20 °C for 1 month, and <6.7% for freeze/thaw cycles (n = 3). The results indicated that the proposed method was rapid, sensitive, and accurate for determination of the three antianginal drugs in human serum. The possible separation mechanism of the method was also discussed, and a model of separation mechanism for the analytes was established.
Comparative efficacy of nifedipine gastrointestinal therapeutic system versus diltiazem when added to beta blockers in stable angina pectoris
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To determine the relative efficacy of nifedipine gastrointestinal therapeutic system (GITS) and diltiazem, 20 patients with angina pectoris and coronary artery disease were studied in a double-blinded, placebo-controlled randomized crossover trial. All patients were taking concomitant β blockers. Efficacy was assessed by symptoms, exercise treadmill testing, and ambulatory ST-segment monitoring at baseline and after 6 weeks on each medication. Mean daily dose was titrated to 119 ± 7 mg (nifedipine GITS) and 342 ± 59 mg (diltiazem). The addition of either nifedipine GITS or diltiazem resulted in a significant reduction in angina frequency, improvement in exercise treadmill duration (7 vs 7 and 8 minutes; baseline vs nifedipine GITS and diltiazem), time to angina onset (4 vs 7 and 7 minutes; baseline vs nifedipine GITS and diltiazem), and time to ST-segment depression (5 vs 6 and 7 minutes; baseline vs nifedipine GITS and diltiazem). There was no significant difference between nifedipine GITS and diltiazem with respect to the magnitude of improvement in anginal symptoms or exercise test parameters. Both nifedipine GITS and diltiazem reduced the overall frequency and duration of ischemic episodes on ambulatory monitoring, but this reduction was not statistically different. Thus, nifedipine GITS and diltiazem at maximally tolerated doses were equally effective at reducing angina and increasing exercise tolerance as β blockers alone.
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Membrane-mediated excessive intracellular calcium accumulation (EICA) is a fundamental pathogenetic event associated with chronic muscle degeneration in patients with Duchenne muscular dystrophy (DMD), and in animals with hereditary muscular dystrophy (HMD). Because of potential Ca²⁺-channel blocking properties, we investigated the relative efficacies of chronic diltiazem (DTZM) (50 mg/kg/d), nifedipine (NFDN) (6 mg/kg/d), and verapamil (VPML) (25 mg/kg/d) therapies in reducing EICA and improving dystrophic pathobiology beginning in 30-day-old male BIO-14.6 strain dystrophic hamsters (DH). Each agent, and sterile distilled water as vehicle control, was given in a single daily oral dose for 180 days to four groups each of DH and BIO-F1B strain normal hamsters (NH). Plasma [Ca] and [Mg]; plasma aldolase (ALD), creatine kinase (CK), and lactate dehydrogenase (LDH) activities; relative cardiac hypertrophy and relative soleus hypertrophy; tissue [Ca] and [Mg] of the heart and rectus femoris muscle, histology of rectus femoris, and overall mortality rate were quantitated. Muscle Mg was not modified in DH, or by any of these agents. NFDN produced significant edema in the soleus and myocardium. During the 6-month therapeutic trial, 45% DH and 18% NH died on VPML, 27% DH and 9% NH on NFDN, and 20% DH controls on distilled water, but none on DTZM; suggesting that DTZM treated DH lived longer than DH controls. Relative efficacy in regulating EICA in both the cardiac and skeletal muscles; plasma ALD, CK, and LDH; and improving associated dystrophic pathobiology was found to be DTZM > > > NFDN > VPML. DTZM appears to be the most effective and safest agent in mitigating EICA in cardiac and skeletal muscles, efflux of intracellular enzymes, histopathology of dystrophic muscle with sporadic necrosis, and chronic muscle degeneration in DH with HMD. DTZM therapy also halted the high morbidity and mortality associated with the dystrophic pathobiology inherent in DH.
Scintigraphic and pharmacokinetic assessment of a multiparticulate sustained release formulation of diltiazem
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The in vivo behaviour of a sustained release multiparticulate form of diltiazem (240 mg) has been evaluated by gamma scintigraphy in eight subjects under fasting or fed conditions. The gastric emptying of the pellet formulation was significantly influenced by the presence of food. Transit through the small intestine was unaffected by food and in the majority of cases, the formulation reached the caecum about 3–4 h after leaving the stomach. Post-prandial administration of the sustained release pellet formulation did not affect the bioavailability of the drug. The type of oral formulation (i.e. solution or pellets) appeared to affect the rate, but not the extent, of absorption with the relative bioavailability (pellets to solution) being greater than 90%.
Determination of serum diltiazem concentrations in a pharmacokinetic study using gas chromatography with electron capture detection
1990, Journal of Pharmaceutical and Biomedical Analysis
An open cross-over randomized clinical trial was performed in nine healthy humans to determine steady-state pharmacokinetics and bioavailability of three oral diltiazem preparations, tablets containing 60 and 90 mg of diltiazem hydrochloride, administered in total daily doses of 180 mg. Serum drug levels were determined by gas chromatography with electron capture detection following a simple extraction procedure. Blood samples were collected before and at several post-dosing intervals after administration of the last dose in steady state, and pharmacokinetic parameters were calculated. The steady-state diltiazem concentrations in sera were determined 48 h after the first dose, and were (mean ±SD): 46.4 ± 28.1, 60.8 ± 36.3 and 36.8 ± 22.6 μg l⁻¹ for Pliva 60, Pliva 90, and Aldizem 90 diltiazem preparations, respectively. The corresponding elimination half-lives were 5.6 ± 2.0, 5.2 ± 1.8 and 6.9 ± 3.2 h; peak concentrations were 88.4 ± 29.5, 153.5 ± 86.5 and 139.2 ± 72.5 μg l⁻¹, and areas under the concentration curves (AUC 12 h) were 477.4 ± 172.5, 989.2 ± 536.3 and 817.9 ± 494.5 μg h l⁻¹ respectively.

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View full text

The pharmacokinetics of diltiazem in healthy American men

Am J Cardiol

Am J Cardiol

J Chromatogr

Antianginal drugs

Calcium, calcium antagonists, and cardiovascular disease

Chest

Critical evaluation of the potential error in pharmacokinetic studies using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve

J Pharmacokinet Biopharm

Haemodynamic effects of a new anti-anginal drug, diltiazem hydrochloride

Arzneim Forsch