Metabolism of the calcium antagonist, mibefradil (POSICOR™, Ro 40-5967). Part II. Metabolism in hepatic microsomes from rat, marmoset, cynomolgus monkey, rabbit and man

Wiltshire, Hugh; Sutton, Blaine M.; Heeps, G.; Betty, A. Maddux; Angus, Derek; Madigan, Michael J.; Sharp, Stephen R

doi:10.1080/004982597240334

Cited by 7 publications

(7 citation statements)

References 11 publications

(17 reference statements)

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“…Metabolism consists of a combination of P450-mediated oxidation, hydrolysis of the ester side chain by CYP3A4 and esterases, and conjugation with glucuronic acid by UDP glucuronosyltransferases (UGTs) (Wiltshire et al, 1997b;Ernst and Kelly, 1998). One of the major hydrolyzed metabolites, Ro 40-5966 ( Fig.…”

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confidence: 99%

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Bui

Quesada²,

Handforth³

et al. 2008

Drug Metab Dispos

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confidence: 99%

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Bui

Quesada²,

Handforth³

et al. 2008

Drug Metab Dispos

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“…This study reported that the AUC (area under the curve) of mibefradil in plasma for the final dose given on day 8 was 7797 ± 1323 ng h/mL [6], equivalent to~11-16 μM. Mibefradil is efficiently processed by cytochrome P450-catalysed hydrolysis and its metabolites typically represent 50-80% of the circulating drugrelated compounds after a single oral dose of 100 mg [5]. Considering that our in vitro studies showed a LogEC 50 around 45-50 μM for mibefradil and that micromolar (≥ 10 μM) concentrations significantly raised [Ca 2+ ] cyt (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Mibefradil, a T-type voltage-gated calcium (Ca 2+ ) channels (Ca v 3.1-3.3) inhibitor, was launched by Roche as Posicor® for the treatment of hypertension and stable angina at doses containing 50-100 mg once a day [1,4]. The maximum plasma circulating levels of mibefradil were around 1 μg/mL after 1-2 h of the single 100 mg dose [4,5]. Although mibefradil has a potent effect on T-type CCA, being 10to 30-fold higher for T-type than L-type [4], adverse clinical outcomes resulted in its withdrawal from the market in 1998 because of drug-drug interactions, sideeffects, and inhibition of cytochrome P450 3A4 [6].…”

Section: Introductionmentioning

confidence: 99%

Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP3 receptor function

et al. 2021

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Mibefradil is a tetralol derivative originally developed as an antagonist of T-type voltage-gated calcium (Ca2+) channels to treat hypertension when used at nanomolar dosage. More recently, its therapeutic application in hypertension has declined and has been instead repurposed as a treatment of cancer cell proliferation and solid tumor growth. Beyond its function as a Cav blocker, the micromolar concentration of mibefradil can stimulate a rise in [Ca2+]cyt although the mechanism is poorly known. The chanzyme TRPM7 (transient receptor potential melastanin 7), the release of intracellular Ca2+ pools, and Ca2+ influx by ORAI channels have been associated with the increase in [Ca2+]cyt triggered by mibefradil. This study aims to investigate the cellular targets and pathways associated with mibefradil’s effect on [Ca2+]cyt. To address these questions, we monitored changes in [Ca2+]cyt in the specialized mouse epithelial cells (LS8 and ALC) and the widely used HEK-293 cells by stimulating these cells with mibefradil (0.1 μM to 100 μM). We show that mibefradil elicits an increase in [Ca2+]cyt at concentrations above 10 μM (IC50 around 50 μM) and a fast Ca2+ increase capacity at 100 μM. We found that inhibiting IP3 receptors, depleting the ER-Ca2+ stores, or blocking phospholipase C (PLC), significantly decreased the capacity of mibefradil to elevate [Ca2+]cyt. Moreover, the transient application of 100 μM mibefradil triggered Ca2+ influx by store-operated Ca2+ entry (SOCE) mediated by the ORAI channels. Our findings reveal that IP3R and PLC are potential new targets of mibefradil offering novel insights into the effects of this drug.

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“…The phenomenon that plasma concentrations of mibefradil rose more than the dosage ratio had been observed in humans previously (Welker et al, 1998). According to a report on the metabolic pathway of mibefradil, oxidative metabolites were major (Wiltshire et al, 1997b). Therefore, this nonlinear pharmacokinetics seemed to occur as a result of the autoinactivation of metabolism of mibefradil by MBI.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Prediction of Mechanism-Based Inhibition Caused by Mibefradil in Rats

Sekiguchi¹,

Kato²,

Takada³

et al. 2011

Drug Metab Dispos

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ABSTRACT:It was previously demonstrated that mibefradil, which shows mechanism-based inhibition in humans, also caused drug-drug interactions (DDIs) with midazolam (MDZ) in rats. In this study, we aimed to quantitatively predict the DDIs observed in rats using a physiologically based pharmacokinetic (PBPK) model from in vitro inactivation parameters. For more precise predictions, contribution ratios of cytochrome P450 (P450) isozymes involved in MDZ metabolism and inactivation parameters of mibefradil against each isozyme were incorporated in the predictive model. The evaluation of metabolic rate using recombinant P450s suggested that CYP3A2 and CYP2C11 contributed to 89 and 11% of MDZ metabolism, respectively. Inactivation studies of mibefradil against the two isozymes showed that the maximal inactivation rate constants (k inact ) were considerable in both isozymes (0.231-0.565 min ؊1 ), whereas the inhibitor concentration producing half the k inact (K I, app ) of CYP3A2 (0.263-0.410 M) was a good deal lower than that for CYP2C11 (6.82-11.4 M). As a result of predicting the DDIs using the PBPK model, predicted increases in areas under the concentration-time curve of MDZ with coadministration of mibefradil (284 and 510% at 6 and 12 mg/kg mibefradil, respectively) closely corresponded to the observed values (226 and 545%, respectively). From those results, it was thought that the construction of a predictive model for DDIs using the PBPK model in detail would enable us to quantitatively predict in vivo DDIs from in vitro data. This approach to predict DDIs on the basis of the contributing isozymes would be important for predicting clinical DDIs of drugs metabolized by multiple enzymes.

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Metabolism of the calcium antagonist, mibefradil (POSICOR™, Ro 40-5967). Part II. Metabolism in hepatic microsomes from rat, marmoset, cynomolgus monkey, rabbit and man

Cited by 7 publications

References 11 publications

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP3 receptor function

Quantitative Prediction of Mechanism-Based Inhibition Caused by Mibefradil in Rats

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