Near-total Reduction in Verapamil Bioavailability by Rifampin

Barbarash, Rick A.; Bauman, Jerry L.; Fischer, James H.; Kondos, George T.; Batenhorst, Randal L.

doi:10.1378/chest.94.5.954

Cited by 45 publications

(24 citation statements)

References 22 publications

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“…In addition, before our mouse treatment study, we conducted a pharmacologic assessment of the rifampin-verapamil drug-drug interaction. Although it is known that concomitant rifampin administration lowers levels of orally administered verapamil by approximately 90% via induction of CYP3A4 in humans (25,26,32), the earlier 2-month mouse study with multidrug-resistant TB infection did not adjust the verapamil dosing for this interaction. Our pharmacologic assessment revealed that, in mice receiving steady-state rifampin, it is necessary to use a verapamil dose of 9.4 mg/kg to achieve a daily AUC equivalent to that achieved with 40 mg/d of verapamil in humans.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

Gupta

Tyagi

Almeida

et al. 2013

Am J Respir Crit Care Med

149

120

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Rationale: A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. Objectives: Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/ pharmacodynamic relationships of verapamil and rifampin coadministration in mice. Methods: Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. Measurements and Main Results: We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone.Conclusions: These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB.Keywords: human equivalent doses; verapamil; efflux; Mycobacterium tuberculosis Tuberculosis (TB), a disease affecting millions of people worldwide, requires treatment of patients with multiple drugs for several months. The complexity and length of therapy has led to the emergence of extensively drug-resistant Mycobacterium tuberculosis, which poses a global threat (1). The limited number of new antimicrobials in the TB drug development pipeline further emphasizes the need for fresh approaches in TB therapy. Repurposing existing approved drugs that may serve as treatmentshortening adjuvants is a promising and relatively efficient approach (2). Efflux pump inhibitors (EPIs) are potential agents in this category, and there have been initial promising reports for licensed agents, such as verapamil, reserpine, and piperine (3).Recently, Adams and colleagues (4) showed that the bacterial efflux pump-encoding gene, Rv1258c promotes intracellular bacterial survival, and may mediate drug tolerance. Addition of verapamil reduced tolerance to rifampin in both M. tuberculosis and Mycobacterium marinum, and incubation of M. marinuminfected macrophages with verapamil reduced intracellular bacterial growth. When verapamil was added to isoniazidand rifampin-treated M. marinum-infected macrophages, it restored antibiotic killing by red...

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Section: Discussionmentioning

confidence: 99%

“…In humans, rifampin causes up to a 10-fold reduction in plasma levels of orally administered verapamil (25,26). To assess the nature of this interaction in mice, we measured mouse plasma verapamil levels after steady-state induction by rifampin for 10 days.…”

Section: Pharmacokinetic Studies and Dose Selection For Verapamil Trementioning

confidence: 99%

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

Gupta

Tyagi

Almeida

et al. 2013

Am J Respir Crit Care Med

149

120

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“…In principle, strong SXR activators should lead to higher levels of CYP3A4, which is involved in the clearance of 60% of clinically relevant drugs (Cholerton et al 1992). For example, rifampicin leads to increased clearance of calcium channel blockers such as nifedipine (Holtbecker et al 1996;Ndanusa et al 1997) and verapamil (Barbarash et al 1988), anti-arhythmics such as pirmenol (Stringer et al 1988), and ␤-blockers such as propranolol (Herman et al 1983), in addition to the steroid interactions mentioned above. It should be noted that, although most CYP3A4 inducers are SXR activators, a few such as cyclosporine A fail to activate SXR.…”

Section: Discussionmentioning

confidence: 99%

SXR, a novel steroid and xenobioticsensing nuclear receptor

Blumberg

Sabbagh²,

Juguilon³

et al. 1998

Genes Dev.

844

765

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An important requirement for physiologic homeostasis is the detoxification and removal of endogenous hormones and xenobiotic compounds with biological activity. Much of the detoxification is performed by cytochrome P-450 enzymes, many of which have broad substrate specificity and are inducible by hundreds of different compounds, including steroids. The ingestion of dietary steroids and lipids induces the same enzymes; therefore, they would appear to be integrated into a coordinated metabolic pathway. Instead of possessing hundreds of receptors, one for each inducing compound, we propose the existence of a few broad specificity, low-affinity sensing receptors that would monitor aggregate levels of inducers to trigger production of metabolizing enzymes. In support of this model, we have isolated a novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), which activates transcription in response to a diversity of natural and synthetic compounds. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P-450 genes and is expressed in tissues in which these catabolic enzymes are expressed. These results strongly support the steroid sensor hypothesis and suggest that broad specificity sensing receptors may represent a novel branch of the nuclear receptor superfamily.[Key Words: Steroid; xenobiotic receptor; nuclear receptor; transcriptional activity] Received July 24, 1998; revised version accepted August 26, 1998. Lipophilic hormones, such as steroids, retinoic acid, thyroid hormone, and vitamin D3, control broad aspects of animal growth, development, and adult organ physiology. The effects of these hormones are mediated by a large superfamily of intracellular receptors that function as ligand-dependent and sequence-specific transcription factors. The nonsteroidal nuclear receptors for thyroid hormone (TR), vitamin D3 (VDR), all-trans retinoic acid (RAR), and fatty acids and eicosanoids (PPAR) form heterodimers with the 9-cis retinoic acid receptor (RXR) that bind bipartite hormone-response elements (HREs) composed of directly repeated half sites related to the sequence AGGTCA (Mangelsdorf and Evans 1995). In contrast, the steroid receptors function as homodimers and bind to palindromic target sequences spaced by three nucleotides . In addition to the known receptors, a large group of structurally related 'orphan' nuclear receptors has been described; that these receptors possess obvious DNA and ligand-binding domains but lack identified ligands . Each has the potential to regulate a distinct endocrine signaling pathway.It is widely viewed that the hormone response is a consequence of the release from an endocrine gland of a ligand that circulates through the blood, and coordinately regulates responses in target tissues by acting through specific nuclear receptors. Hormone responsiveness is dependent on the ability to rapidly clear ligand from the blood and the body so that, in absence of a stimulus, target tissues re...

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“…So far, the complex pattern of verapamil oxidative metabolism has been extensively studied ( Fig. Data in parentheses indicate the amount of metabolite excreted in urine (Eichelbaum et al 1978) rail metabolism (Kroemer et al 1992) and characterized some of the respective P 450 enzymes involved (Fuhr et al 1992;Kroemer et al 1993): the identification of the enzymes catalyzing the two main metabolic routes of veraparail, namely the N-demethylation by C Y P 3 A 4 and the Ndealkylation by C Y P 3 A 4 and 1A2, has provided the molecular base for our understanding of the metabolic in vivo interactions of verapamil with other C Y P 3 A 4 or C Y P 1 A 2 substrates like cyclosporine (Lindholm and Henrissons 1987), theophylline (Abemethy et al 1988) and caffeine (Fuhr et al 1992) or inducers like phenobarbital (Rutledge et al 1988) and rifampicin (Barbarash et al 1988). Previous studies of the in vitro metabolism of verapamil have evaluated the contribution of the individual pathways to overall verapa- Fig.…”

Section: Introductionmentioning

confidence: 99%

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans

Busse

Cosme

Beaune

et al. 1995

Naunyn-Schmiedeberg's Arch Pharmacol

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The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile+ ++] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile], and verapamil N-demethylation (formation of norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopro pyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-isopro pyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (III) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18. In human liver microsomes (n=4), the intrinsic clearance (CLint), as derived from the ratio of Vmax/Km, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9 +/- 1.0 vs 2.4 +/- 0.6 ml*min-1*g-1, mean+/-SD; p<0.05), S-verapamil (16.8 +/- 3.3 vs 2.2 +/- 1.2 ml* min-1*g-1, p<0.05) and R-verapamil (12.1 +/- 2.9 vs 3.6 +/- 1.3 ml*min-1*g-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CLint of D-703 formation in human liver microsomes showed a modest but significant degree of stereoselectivity (p<0.05) with a S/R-ratio of 1.41 +/- 0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5 +/- 4.5% and 45%, that of D-702 by 52.7 +/- 7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703. In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.

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Near-total Reduction in Verapamil Bioavailability by Rifampin

Cited by 45 publications

References 22 publications

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

SXR, a novel steroid and xenobioticsensing nuclear receptor

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans

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