Steady State Verapamil Tissue Distribution in the Dog: Differing Tissue Accumulation

Schwartz, Janice B.; Todd, Elizabeth L.; Abernethy, Darrell; Mitchell, Jerry R.

doi:10.1159/000138185

Cited by 9 publications

(8 citation statements)

References 6 publications

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“…However the elimination half‐lives of verapamil in plasma and tissues do not differ . One study on dogs reported the following order of accumulation in various tissues: lung ≥ kidney > spleen > ventricular myocardium = liver > atrial myocardium > cerebral cortex > fat = skeletal muscle .…”

Section: Discussionmentioning

confidence: 99%

Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish

Nallani

Edziyie

Paulos

et al. 2016

Enviro Toxic and Chemistry

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The present study examined the bioconcentration of 2 basic pharmaceuticals: verapamil (a calcium channel blocker) and clozapine (an antipsychotic compound) in 2 fresh water fishes, fathead minnow and channel catfish. In 4 separate bioconcentration factor (BCF) experiments (2 chemicals × 1 exposure concentration × 2 fishes), fathead minnow and channel catfish were exposed to 190 μg/L and 419 μg/L of verapamil (500 μg/L nominal) or 28.5 μg/L and 40 μg/L of clozapine (50 μg/L nominal), respectively. Bioconcentration factor experiments with fathead consisted of 28 d uptake and 14 d depuration, whereas tests conducted on catfish involved a minimized test design, with 7 d each of uptake and depuration. Fish (n = 4-5) were sampled during exposure and depuration to collect different tissues: muscle, liver, gills, kidneys, heart (verapamil tests only), brain (clozapine tests only), and blood plasma (catfish tests only). Verapamil and clozapine concentrations in various tissues of fathead and catfish were analyzed using liquid chromatography-mass spectrometry. In general, higher accumulation rates of the test compounds were observed in tissues with higher perfusion rates. Accumulation was also high in tissues relevant to pharmacological targets in mammals (i.e. heart in verapamil test and brain in the clozapine test). Tissue-specific BCFs (wet wt basis) for verapamil and clozapine ranged from 0.7 to 75 and from 31 to 1226, respectively. Tissue-specific concentration data were used to examine tissue-blood partition coefficients.

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Section: Discussionmentioning

confidence: 99%

Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish

Nallani

Edziyie

Paulos

et al. 2016

Enviro Toxic and Chemistry

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“…Of these efflux-blocking drugs, verapamil appeared the most promising for further study. It has a long track record of broad and relatively safe clinical use [26,27], and animal studies show it to be 40-to 80-fold concentrated in the lungs [28,29]. In contrast, the other inhibitors were less attractive because (1) nontoxic plasma levels in humans are far below the levels needed to reverse tolerance in vitro and pulmonary concentration is doubtful ( piperine [30]) or (2) potential for significant adverse reactions (thioridazine).…”

Section: Drugs Known To Inhibit Bacterial Efflux Pumps Reverse Macropmentioning

confidence: 99%

Verapamil, and Its Metabolite Norverapamil, Inhibit Macrophage-induced, Bacterial Efflux Pump-mediated Tolerance to Multiple Anti-tubercular Drugs

Adams

Szumowski

Ramakrishnan

2014

The Journal of Infectious Diseases

119

121

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Drug tolerance likely represents an important barrier to tuberculosis treatment shortening. We previously implicated the Mycobacterium tuberculosis efflux pump Rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. In this study, we infected the human macrophage-like cell line THP-1 with drug-sensitive and drug-resistant M. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, PA-824, linezolid, and bedaquiline. Multiple efflux pump inhibitors in clinical use for other indications reversed tolerance to isoniazid and rifampicin and slowed intracellular growth. Moreover, verapamil reduced tolerance to bedaquiline and moxifloxacin. Verapamil's R isomer and its metabolite norverapamil have substantially less calcium channel blocking activity yet were similarly active as verapamil at inhibiting macrophage-induced drug tolerance. Our finding that verapamil inhibits intracellular M. tuberculosis growth and tolerance suggests its potential for treatment shortening. Norverapamil, R-verapamil, and potentially other derivatives present attractive alternatives that may have improved tolerability.

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“…In animal experiments propranolol has been shown to accumulate extensively in the lungs and skeletal muscles [Bianchetti et al 1980;Schneck et al 1977;Takahashi et al 1990]. Verapamil also accumulates in the lungs and less in skeletal muscle [Hamann et al 1983;Schwartz et al 1986;Todd and Abernethy 1987]. Atenolol accumulation in the lungs is lower than that of propranolol when administered in an equimolar dose [Lemmer et al 1985;Davies and McAinsh t986].…”

Section: Discussionmentioning

confidence: 99%

Exercise and the pharmacokinetics of propranolol, verapamil and atenolol

Baak¹,

Mooij²,

Schiffers³

1992

Eur J Clin Pharmacol

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The volumes of distribution of the beta-adrenoceptor blocking agents propranolol and atenolol, and the calcium antagonist verapamil, during exercise have been investigated. Changes in the plasma concentrations of atenolol and propranolol during exhaustive exercise at 70% of maximal aerobic power were compared after 1 week of oral treatment (propranolol 80 mg b.d. and atenolol 100 mg once daily) in 12 healthy volunteers. In a second study the effect of 10 min exercise at 50% of maximal aerobic power on steady state plasma concentrations of propranolol, atenolol and verapamil was compared in 7 healthy subjects. The drugs were administered by a continuous intravenous infusion. The plasma concentration of atenolol was not changed by exercise in either study, but the plasma concentrations of propranolol and verapamil were significantly increased in both studies. However, after correction for changes in plasma volume during exercise, the plasma propranolol concentration was not significantly elevated in the second study. From the results it is concluded that exercise led to a reduction in the volume of distribution of propranolol during prolonged exercise (25 min) at 70% Wmax, which was not clearly demonstrable during 10 min exercise at 50% Wmax. The volume of distribution of verapamil was reduced during 10 min exercise at 50% Wmax. No change in the volume of distribution of atenolol during exercise could be shown. The changes in the volumes of distribution of propranolol and verapamil during exercise may contribute to preventing an increase in the half-life of these drugs in patients performing prolonged physical exercise.

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Steady State Verapamil Tissue Distribution in the Dog: Differing Tissue Accumulation

Cited by 9 publications

References 6 publications

Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish

Bioconcentration of two basic pharmaceuticals, verapamil and clozapine, in fish

Verapamil, and Its Metabolite Norverapamil, Inhibit Macrophage-induced, Bacterial Efflux Pump-mediated Tolerance to Multiple Anti-tubercular Drugs

Exercise and the pharmacokinetics of propranolol, verapamil and atenolol

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