Decreased Binding of Verapamil to Plasma Proteins in Patients with Liver Disease

Giacomini, Kathleen M.; Massoud, Neil; Wong, Fee Mi; Giacomini, John C.

doi:10.1097/00005344-198409000-00028

Cited by 20 publications

(8 citation statements)

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“…This finding is reasonable because verapamil and norverapamil are both lipophilic compounds. Since the efflux process outcompeted the biliary secretion (CL (Yamano et al, 2000), but was lower than that in healthy subjects (0.09) (Giacomini et al, 1984).…”

Section: Discussionmentioning

confidence: 98%

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

Yang

Tang

et al. 2015

Drug Metab Dispos

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We applied physiologically based pharmacokinetic (PBPK) modeling to study the dose-dependent metabolism and excretion of verapamil and its preformed metabolite, norverapamil, to unravel the kinetics of norverapamil formation via N-demethylation. Various initial verapamil (1, 50, and 100 mM) and preformed norverapamil (1.5 and 5 mM) concentrations, perfused at 12 ml/min, were investigated in the perfused rat liver preparation. Perfusate and bile were collected over 90 minutes, and livers were harvested at the end of perfusion for high-performance liquid chromatography analysis. After correction for the adsorption of 10%-25% dose verapamil and norverapamil onto Tygon tubing and binding to albumin and red blood cell, fitting of verapamil and formed and preformed norverapamil data with ADAPT5 revealed nonlinearity for protein binding, N-demethylation ) decreased with the dose (8.16-10.2 ml/min), with values remaining high relative to perfusate blood flow rate among the doses. The hepatic clearance of preformed norverapamil (11 ml/min) remained unchanged for the concentrations studied and approximated perfusate blood flow rate, suggesting a high norverapamil extraction ratio. The fractional formation of norverapamil and biliary excretion of verapamil based on fitted constants were 31.1% and 0.64% of CL VER L , respectively. Enantiomeric disposition and autoinhibition of verapamil failed to perturb these estimaties according to PBPK modeling, due to the low values of the Michaelis-Menten constant, K m , and inhibition parameter, k I .

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Section: Discussionmentioning

confidence: 98%

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

Yang

Tang

et al. 2015

Drug Metab Dispos

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“…However, Broccatelli and coworkers argued that verapamil is a BBB+ drug, for example, based on the human total brain/plasma ratio (K p,brain ) of 0.55 (Sasongko et al, 2005), ignoring the unbound brain/plasma ratio of 0.053 in rat (Friden et al, 2009) and 0.10 in human. Note that unbound brain/plasma ratio in human is estimated using K p,brain of 0.55 (Sasongko et al, 2005), with unbound fraction in human plasma of 0.099 (Giacomini et al, 1984) and unbound fraction in rat brain of 0.0185 (Friden et al, 2009) since it has been demonstrated that brain tissue binding is species-independent (Di et al, 2011). Moreover, (R)-[11C]verapamil is used as a clinical probe for P-gp efflux at the BBB in positron emission tomography studies (Syvanen and Hammarlund-Udenaes, 2010).…”

Section: Criteria For Bbb Class Assignmentmentioning

confidence: 99%

In Vitro P-glycoprotein Efflux Ratio Can Predict the In Vivo Brain Penetration Regardless of Biopharmaceutics Drug Disposition Classification System Class

2013

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P-glycoprotein (P-gp) is expressed at the blood-brain barrier (BBB) and restricts the penetration of its substrates into the central nervous system (CNS). In vitro substrate assessment for P-gp is frequently used to predict the in vivo relevance of P-gp-mediated efflux at the BBB. We have conducted a comprehensive review of literature focusing on the in vitro-in vivo correlation of P-gp efflux ratio (ER), and demonstrated that in vitro substrates of P-gp are also in vivo substrates at the BBB. It was of note that the in vitro ER in the MDCK-MDR1 cell line from National Institutes of Health was found to be a better predictor of in vivo ER than that from Netherlands Cancer Institute, with r 2 values of 0.813 and 0.531, respectively. Recently, a research group proposed that 98% of Biopharmaceutics Drug Disposition Classification System (BDDCS) class 1 drugs can penetrate the brain even when those compounds are shown as P-gp substrates in vitro. However, our data analysis suggested that in vitro ER can predict the in vivo brain penetration regardless of the class in BDDCS. Considering that very few marketed CNS drugs are in vivo substrates for P-gp, the in vitro substrate assessment of P-gp should be used in the early stages of drug discovery to select compounds that are most likely to penetrate the CNS to exert their pharmacologic action.

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“…This free concentration is higher in the presence of chloride and calcium ions . Furthermore, in another study, a substantial effect of pH on the binding of verapamil to plasma proteins was observed (Giacomini et al, 1984).…”

Section: Phmentioning

confidence: 91%

“…For clinical monitoring, at any given total concentration, the unbound concentration would be ∼ 60% higher in patients with liver disease, and caution should be exercised in the administration of verapamil to patients with liver disease (Giacomini et al, 1984).…”

Section: Hepatic Diseasesmentioning

confidence: 99%

Protein Binding of Drugs

Kotsiou

Tesseromatis²

2011

Oral Bioavailability

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Decreased Binding of Verapamil to Plasma Proteins in Patients with Liver Disease

Cited by 20 publications

References 0 publications

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

In Vitro P-glycoprotein Efflux Ratio Can Predict the In Vivo Brain Penetration Regardless of Biopharmaceutics Drug Disposition Classification System Class

Protein Binding of Drugs

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