Verapamil kinetics in normal subjects and patients with coronary artery spasm

Freedman, Ben; Richmond, David; Ashley, John J.; Kelly, David T.

doi:10.1038/clpt.1981.216

Cited by 112 publications

(52 citation statements)

References 3 publications

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“…In patients, repeat dosing has led to a significant increase in the plasma verapamil halflife (Freedman et al, 1981;Shand et al, 1981;Schwartz et al, 1982). Both formulations led to an increase in verapamil AUC on repeat dosing and it has been suggested that this effect results from impaired clearance or, less likely, a further distribution of verapamil into deeper tissue compartments during repeat dosing .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of two formulations of verapamil.

Hla

Henry

Latham

1987

Brit J Clinical Pharma

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The pharmacokinetics and pharmacodynamics of sustained release verapamil were compared with the conventional formulation in 10 healthy adult volunteers after single and multiple dosing. The mean time of maximum plasma concentrations of verapamil were significantly prolonged and the absorption rate constants significantly reduced after sustained release verapamil on both day 1 and day 10. On day 10 there was no significant difference between formulations in the relative bioavailability of verapamil. However, the area under the plasma concentration‐time curve and maximum concentration (Cmax) for both formulations increased significantly with repeat dosing. On day 10, the difference in Cmax between formulations was significant. The day 10 mean peak/trough plasma verapamil concentration ratio was significantly less following the sustained release dose form. The mean PR interval was significantly prolonged by both formulations on day 1 and day 10. There were no differences between formulations other than a significantly longer PR interval following the conventional formulation 2 h after dosing on day 10.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of two formulations of verapamil.

Hla

Henry

Latham

1987

Brit J Clinical Pharma

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“…This phenomenon may contribute significantly to the considerable interindividual variation in CYP3A-based drug interactions. Second, verapamil itself is a CYP3A substrate, and upon repeated dosing, autoinhibition results in increases in oral bioavailability and decreased systemic clearance (Freedman et al, 1981;Eichelbaum and Somogyi, 1984). Thus, clinical responses, both desirable (e.g., blood pressure lowering and heart rate control) and undesirable (e.g., hypotension and heart block), may differ between CYP3A5 expressers and nonexpressers.…”

Section: Discussionmentioning

confidence: 99%

Differential Mechanism-Based Inhibition of Cyp3a4 and Cyp3a5 by Verapamil

Wang¹,

Jones²,

Hall³

2005

Drug Metab Dispos

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ABSTRACT:The genetic basis for polymorphic expression of CYP3A5 has been recently identified, but the significance of CYP3A5 expression is unclear. The purpose of this study is to quantify the capability of verapamil, a mechanism-based inhibitor of CYP3A, and its metabolites to inhibit the activities of CYP3A4 and CYP3A5, and to determine whether CYP3A5 expression in human liver microsomes alters the inhibitory potency of verapamil. Testosterone 6␤-hydroxylation or midazolam 1-hydroxylation was used to quantify CYP3A activity. The possibility that verapamil and its metabolites form metabolic-intermediate complex (MIC) with CYP3A was assessed using dual beam spectrophotometry. Verapamil and Ndesalkylverapamil (D617) were found to have little inhibitory effect on cDNA-expressed CYP3A5 activity and did not form a MIC with cDNA-expressed CYP3A5 as indicated by the appearance of the CYP3A4 and CYP3A5 are the most abundant CYP3A enzymes in adult human liver and small intestine, and they share 83% identity in amino acid sequence (Aoyama et al., 1989). These two CYP3A enzymes have similar substrate specificity and are responsible for metabolism of more than 50% of administered drugs that are eliminated through the liver (Thummel and Wilkinson, 1998). CYP3A substrates show large interindividual variations in oral bioavailability and systemic clearance. These variations are thought to be contributed by interindividual differences in CYP3A activities and their expression.In addition to inducers and inhibitors, genetic variation is considered to be one of the major factors that contribute to interindividual variability (Ozdemir et al., 2000). CYP3A5 has been found in approximately 10 to 30% of livers from white adults, and the genetic basis for CYP3A5 polymorphic expression has been identified (Wrighton et al., 1989;Kuehl et al., 2001). An A3 G substitution within intron 3 of the CYP3A5 gene accounts for much of the variability in CYP3A5 content found in the human liver and intestine (Kuehl et al., 2001). Individuals who have at least one CYP3A5*1 allele, the wild-type allele, produce high levels of CYP3A5 protein in their livers and intestines, whereas those who are homozygous for the CYP3A5*3 allele, the variant allele, produce very low or no CYP3A5 protein. The significance of CYP3A5 phenotypes is unclear because CYP3A4 and CYP3A5 have similar substrate specificity and no CYP3A5-specific probe substrates or inhibitors are available. One study found that, for individuals who have at least one CYP3A5*1 allele, CYP3A5 represents at least 50% of the total hepatic CYP3A content, whereas others found that CYP3A5 represents only 15 to 30% of the total CYP3A protein (Wrighton et al., 1989;Lin et al., 2002;Westlind-Johnsson et al., 2003). It has been suggested that individual differences in CYP3A5 may contribute to the interindividual variability in CYP3A activity and their susceptibility to drug interactions (Gibbs et al., 1999;Xie et al., 2004).Verapamil is a calcium channel blocker widely used in the treatment of angina pector...

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“…This hypothesis is consistent with several literature reports demonstrating the association between inhibitory metabolites and time-and dose-dependent pharmacokinetic alterations. Propranolol (Wood et al, 1978; Narimatsu et al, 2001), verapamil (Freedman et al, 1981;Shand et al, 1981;Ma et al, 2000;Wang et al, 2004), and diltiazem (Höglund and Nilsson, 1989;Ma et al, 2000;Yeo and Yeo, 2001) all form metabolites capable of MBI, and exhibit time-dependent increases in exposure after multiple dosing. Whereas in vitro data suggest that inhibition of CYP3A by M2 is the most probable cause for the time-dependent pharmacokinetics, the hypothesis has to be considered in the context of the low plasma exposures of this metabolite (Table 3).…”

Section: Discussionmentioning

confidence: 99%

An Inhibitory Metabolite Leads to Dose- and Time-Dependent Pharmacokinetics of (R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in Human Subjects After Multiple Dosing

Tonn¹,

Wong²,

Wong³

et al. 2008

Drug Metab Dispos

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(R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-XAMG 487 (Fig. 1) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist . Clinical testing of AMG 487 revealed dose-and timedependent pharmacokinetic changes that were characterized by greater than anticipated increases in AMG 487 concentrations during multiple ascending dose studies (unpublished data). These results were not anticipated based on single-dose experiments that demonstrated near proportional increases in AMG 487 AUC and maximum plasma concentration (C max ) with doses ranging between 25 and 1100 mg (Floren et al., 2003). Moreover, mean terminal half-lives, ranging from 7.9 to 14 h, which were independent of dose (unpublished data), suggested minimal accumulation after once-daily dosing.Assuming linear pharmacokinetics, the rate and extent of accumulation at steady state can be readily predicted on the basis of the Parts of this work were previously presented as follows:

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Verapamil kinetics in normal subjects and patients with coronary artery spasm

Cited by 112 publications

References 3 publications

Pharmacokinetics and pharmacodynamics of two formulations of verapamil.

Pharmacokinetics and pharmacodynamics of two formulations of verapamil.

Differential Mechanism-Based Inhibition of Cyp3a4 and Cyp3a5 by Verapamil

An Inhibitory Metabolite Leads to Dose- and Time-Dependent Pharmacokinetics of (R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in Human Subjects After Multiple Dosing

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