Near-total Reduction in Verapamil Bioavailability by Rifampin: Electrocardiographic Correlates

doi:10.1378/chest.94.5.954

Chest

Volume 94, Issue 5, November 1988, Pages 954-959

https://doi.org/10.1378/chest.94.5.954 Get rights and content

We evaluated the significance of the interaction between rifampin and verapamil in six volunteers who received single doses of verapamil, 10 mg intravenously (IV), then 120 mg orally two days later. Subjects were then given rifampin, 600 mg orally every day for 15 days. After 13 and 15 days of rifampin therapy, the IV and oral doses of verapamil were repeated. Electrocardiograms (ECG) were done and serum verapamil and norverapamil concentrations measured before and for 12 h after each dose. For IV verapamil, there was a small decrease in area under the serum concentration-time curve and an increase in clearance after rifampin therapy (p<0.05). There were no changes in elimination half-life, volume of distribution, or AUC for percentage of change in P-R interval-time curve (AUC_PR). For oral verapamil, there were marked decreases in peak concentration, AUC, oral bioavailability (all p<0.005), and AUC_PR (p<0.001) after rifampin treatment. There were no changes in time to peak concentration or elimination half-life. For oral verapamil, significant P–R interval prolongation occurred only before treatment with rifampin. The decrease in oral bioavailability and the abolition of ECG response confirm that a highly significant drug interaction exists between rifampin and verapamil given orally but not intravenously

Section snippets

Subjects

Six healthy volunteers (four men, two women), 24 to 37 years old, were studied. All were in excellent health with normal cardiac, renal, and hepatic function judging from results of physical examination, 12-lead ECG, and routine laboratory tests. All subjects were nonsmokers, drank alcohol only occasionally, and did not receive medications for at least two weeks before the study. They were asked to abstain totally from alcohol and drugs other than verapamil and rifampin during the

Pharmacokinetic Effects

For IV verapamil, the serum drug concentration vs time curves were similar before and after treatment with rifampin (Fig 1). The verapamil serum concentrations after the IV dose were best described by a two-compartment model. A small (18 percent) but statistically significant decrease in mean AUC (p<0.05) and a corresponding increase in mean C1 (p<0.05) were observed after rifampin therapy (Table 1). There were no significant changes in the Vss or T½.

For oral verapamil, a 93 percent reduction

DISCUSSION

The present study demonstrates that treatment with rifampin greatly decreases the bioavailability of orally administered verapamil in healthy volunteers. As expected, reduced verapamil bioavailability was accompanied by a significant decrease in the cardiovascular effect of the drug. In the presence of rifampin, oral verapamil therapy caused virtually no change in the P–R interval. While rifampin produced a small increase in verapamil clearance following IV dosing, no significant attenuation of

ACKNOWLEDGMENT

We wish to thank Allan S. Jaffe, M.D., for his helpful advice and careful review of this manuscript. We would also like to thank Vanessa Redding for her expert secretarial assistance.

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Several reports demonstrated that rifampicin affected pharmacokinetics of victim drugs following oral more than intravenous administration. We aimed to establish a semi-physiologically based pharmacokinetic (semi-PBPK) model involving both enzyme and transporter turnover to simultaneously predict pharmacokinetic interaction of rifampicin with oral versus intravenous substrates of cytochrome P450 (CYP) 3A4/P‑glycoprotein (P-GP) in human. Rifampicin was chosen as the CYP3A /P-GP inducer. Thirteen victim drugs including P-GP substrates (digoxin and talinolol), CYP3A substrates (alfentanil, midazolam, nifedipine, ondansetron and oxycodone), dual substrates of CYP3A/P-GP (quinidine, cyclosporine A, tacrolimus and verapamil) and complex substrates (S-ketamine and tramadol) were chosen to investigate drug-drug interactions (DDIs) with rifampicin. Corresponding parameters were cited from literatures. Before and after multi-dose of oral rifampicin, the pharmacokinetic profiles of victim drugs for oral or intravenous administration to human were predicted using the semi-PBPK model and compared with the observed values. Contribution of both CYP3A and P-GP induction in intestine and liver by rifampicin to pharmacokinetic profiles of victim drugs was investigated. The predicted pharmacokinetic profiles of drugs before and after rifampicin administration accorded with the observations. The predicted pharmacokinetic parameters and DDIs were successful, whose fold-errors were within 2. It was consistent with observations that the DDIs of rifampicin with oral victim drugs were larger than those with intravenous victim drugs. DDIs of rifampicin with CYP3A or P-GP substrates following oral versus intravenous administration to human were successfully predicted using the developed semi-PBPK model.
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Cytochrome P450 (CYP) 3A induction-mediated drug–drug interaction (DDI) is one of the major concerns in drug development and clinical practice. The aim of the present study was to develop a novel mechanistic physiologically based pharmacokinetic (PBPK)-enzyme turnover model involving both intestinal and hepatic CYP3A induction to quantitatively predict magnitude of CYP3A induction-mediated DDIs from in vitro data. The contribution of intestinal P-glycoprotein (P-gp) was also incorporated into the PBPK model. First, the pharmacokinetic profiles of three inducers and 14 CYP3A substrates were predicted successfully using the developed model, with the predicted area under the plasma concentration–time curve (AUC) [area under the plasma concentration–time curve] and the peak concentration (C_max) [the peak concentration] in accordance with reported values. The model was further applied to predict DDIs between the three inducers and 14 CYP3A substrates. Results showed that predicted AUC and C_max ratios in the presence and absence of inducer were within twofold of observed values for 17 (74%) of the 23 DDI studies, and for 14 (82%) of the 17 DDI studies, respectively. All the results gave us a conclusion that the developed mechanistic PBPK-enzyme turnover model showed great advantages on quantitative prediction of CYP3A induction-mediated DDIs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2819–2836, 2013
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Low level impurities often reside in active pharmaceutical ingredients (API). Some of these impurities are potentially genotoxic since reactive intermediates are used in the synthetic route for the production of API. Routine mutagenicity testing is conducted in support of clinical trials with the intent to identify genotoxic hazards associated with API. Depending on the amount of impurity present in the API tested, the potency of the impurities and the relative sensitivity of the Ames assay, it is possible that mutagenicity associated with the presence of genotoxic impurities could also be detected while testing API. Therefore, we evaluated published data and generated new information to understand the sensitivity of the Ames assay. Based on a literature survey of approximately 450 mutagens, it was estimated that 85% of mutagens are detected at concentrations of 250 μg/plate or less. Based on this estimate, most mutagens should be detected in an Ames assay testing API concentrations up to 5000 μg/plate if present at a 5% or greater concentration. Data from experiments where several direct and indirect-acting mutagens were spiked into representative API further support the literature-based evaluation. Some limitations of this approach, including toxicity of API and competing metabolism are discussed.
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Cytochrome P450 (CYP) enzymes, which metabolize numerous drugs, are expressed both in liver and in extrahepatic tissues. CYP3A4 for example is present and inducible by rifampin in epithelial cells of the gastrointestinal tract. It has been shown that such prehepatic metabolism contributes substantially to total clearance of CYP3A4 substrates (e.g., cyclosporine) before and even more pronounced during enzyme induction. We examined the effect of enzyme induction on prehepatic and hepatic metabolism of the model compound R/S-verapamil after simultaneous oral and intravenous administration using a stable isotope technology. This approach allows us to exclude intraindividual day-to-day variability and is therefore suitable to quantitatively assess prehepatic extraction of high-clearance drugs. Moreover, because verapamil is administered as a race-mate with the S-enantiomer being preferentially metabolized, we investigated the influence of induction on stereoselectivity of prehepatic and hepatic metabolism. Eight male volunteers received 120 mg of racemic verapamil bid for 24 days. Rifampin (600 mg daily) was given from day 5 to day 16. Systemic clearance and bioavailability of the verapamil enantiomers were determined by coadministering deuterated verapamil intravenously on day 4, on day 16, and on day 24. Effects of verapamil on atrioventricular conduction after oral and intravenous (iv) administration were assessed by measuring the maximum PR-interval prolongation Rifampin increased the systemic clearance of the active S-verapamil 1.3-fold (P < .001). In contrast, rifampin increased the apparent oral clearance of S- verapamil 32-fold (P < .001) and decreased its bioavailability 25-fold (P < .001), with partial recovery after rifampin withdrawal (P < .01). With rifampin, the effect of oral verapamil on atrioventricular conduction was nearly abolished (P < .01), whereas no significant changes were observed after intravenous administration. Induction caused a considerable reduction of stereoselectivity after both intravenous and oral administration (P < .001). Rifampin altered the pharmacokinetics and the pharmacological effects of verapamil to a much greater extent after oral administration compared with intravenous administration. These data clearly indicate that prehepatic metabolism of verapamil (presumably in the gut wall) is preferentially induced compared with hepatic metabolism and that stereoselectivity of verapamil metabolism is affected by induction. (Hepatology 1996 Oct;24(4):796-801)
Toxic effects and drug interactions of antimycobacterial therapy
1995, Clinics in Dermatology
Impact of food on the pharmacokinetics and electrocardiographic effects of sustained release verapamil in normal subjects
1992, The American Journal of Cardiology
To evaluate the impact of food on the pharmacokinetics and electrocardiographic effects of sustained release (SR) verapamil tablets, 9 healthy men each received 3 single doses of verapamil in a randomized, crossover manner: 10 mg of intravenous verapamil, 240 mg SR verapamil on an empty stomach, and 240 mg SR verapamil with a standardized meal. PR intervals and racemic verapamil serum concentrations were measured serially over 30 hours after administration. The time to peak concentration was longer (7.5 ± 3.0 vs 4.4 ± 2.3 hours), resulting in a lower peak verapamil serum concentration (118 ± 43 vs 175 ± 50 ng/ml) when SR verapamil was administered with food (p < 0.05). Food tended to decrease the bioavailability of SR verapamil (34 ± 12 vs 49 ± 14%), although this difference did not reach statistical significance (p = 0.065). Precipitous or exaggerated release of verapamil from the SR tablet was not observed in any subject during the fasting state. Prolongation of the PR interval paralleled these alterations in serum concentration. The maximal change in the PR interval was greater (21 ± 8 vs 14 ± 5%; p < 0.05) when SR verapamil was given in the fasting state. Although an exaggerated verapamil release or effect was not observed, food significantly altered the absorption and electrocardiographic effects of a single dose of SR verapamil. Manipulation of the administration condition may be helpful in achieving desired outcomes.

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Supported in part by grant 911, Campus Research Board, University of Illinois at Chicago Health Sciences Center.

Presented in part at the 37th Annual Scientific Session of the American College of Cardiology, Atlanta, Georgia, March 27-31, 1988.

Manuscript received February 10; revision accepted April 19.

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Chest

Clinical InvestigationsNear-total Reduction in Verapamil Bioavailability by Rifampin: Electrocardiographic Correlates

Section snippets

Subjects

Pharmacokinetic Effects

DISCUSSION

ACKNOWLEDGMENT

J Chromatogr

Am J Cardiol

Am Heart J

Rifampin

Effects of intravenous and chronic oral verapamil administration in patients with supraventricular tachyarrhythmias

Circulation

Calcium antagonists for chronic stable angina pectoris

Am J Cardiol

Calcium antagonists for Prinzmetal's variant angina, unstable angina and silent myocardial ischemia: therapeutic tool and probe for identification of pathophysiologic mechanisms

Am J Cardiol

Role of calcium antagonists in systemic hypertension

Am J Cardiol

Calcium modulators: future agents, future uses

Drug Intell Clin Pharm

Verapamil-rifampin interaction

Drug Intell Clin Pharm

Reduction of bioavailability of verapamil by rifampin [Letter]

N Engl J Med

The influence of antituberculous drugs on the plasma level of verapamil

Eur J Clin Pharmacol

Rifampin drug interactions

Arch Intern Med

Update on rifampin interactions

Arch Intern Med

Clinical Investigations
Near-total Reduction in Verapamil Bioavailability by Rifampin: Electrocardiographic Correlates