N‐monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives.

Montamat, Stephen C.; Abernethy, Darrell R.

doi:10.1111/j.1365-2125.1987.tb03160.x

Cited by 38 publications

(10 citation statements)

References 12 publications

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“…This conclusion is supported by the facts that the observed free plasma concentrations of MA are much lower than its K i (Mayhew et al, 2000), and plasma levels of MD appear to be negligible (Molden et al, 2003). In addition, a prolonged half-life of diltiazem was observed in hypertension patients taking multiple doses (Montamat and Abernethy, 1987), consistent with a time-dependent autoinactivation of diltiazem metabolism. In fact, CYP3A is the major isoform responsible for N-demethylation reactions of diltiazem (Sutton et al, 1997).…”

Section: Discussionsupporting

confidence: 70%

Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A

Zhao

Lee

Kunze³

2007

Drug Metab Dispos

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ABSTRACT:Kinetic parameters (k inact and K I ) obtained in microsomes are often used to predict time-dependent inactivation. We previously reported that microsomal inactivation kinetic parameters of diltiazem underpredicted CYP3A inactivation in hepatocytes. In this study, we evaluated the contributions of inactivation and reversible inhibition of CYP3A by diltiazem and its N-desmethyl (MA) and N,N-didesmethyl (MD) metabolites. In human liver microsomes, MA was a more potent time-dependent inactivator of CYP3A than its parent drug, with apparent k inact approximately 4-fold higher than that of diltiazem at a microsomal protein concentration of 0.2 mg/ml. MD did not inactivate CYP3A. Inactivation of CYP3A by diltiazem was dependent on microsomal protein concentration (25, 36, and 41% decrease in CYP3A activity at 0.2, 0.4, and 0.8 mg/ml microsomal protein, respectively, incubated with 10 M diltiazem over 20 min), whereas inactivation by MA did not seem to be protein concentration-dependent. MA and MD were reversible inhibitors of CYP3A with competitive K i values of 2.7 and 0.2 M, respectively. In cryopreserved hepatocytes incubated with diltiazem, time-dependent loss of CYP3A was accompanied by increased formation of MA and MD, with the MA level similar to its K I at higher diltiazem concentrations. In addition, the metabolites appeared to be accumulated inside the cells. In summary, timedependent CYP3A inactivation by MA seems to be the major contributor responsible for the loss of CYP3A in human liver microsomes and human hepatocytes incubated with diltiazem. These findings suggest that prediction of CYP3A loss based solely on microsomal inactivation parameters of parent drug may be inadequate.The calcium channel blocker diltiazem is extensively metabolized via multiple pathways including N-demethylation, O-demethylation, and deacetylation (Fig. 1). The demethylation pathways are mediated by cytochrome P450 enzymes primarily in the liver, whereas deacetylation is believed to be carried out by esterases in multiple tissues (Homsy et al., 1995;Sutton et al., 1997). N-Desmethyl diltiazem (MA) is the major metabolite that undergoes further N-demethylation process to form N,N-didesmethyl diltiazem (MD). It has been shown that diltiazem caused clinically significant drug-drug interactions by decreasing the elimination of substrates through inhibition of CYP3A (Jones and Morris, 2002;Jerling et al., 2005). The cause of inhibition has been attributed to both diltiazem and its metabolites. In human liver microsomes (HLMs), MA and MD appeared to competitively inhibit testosterone 6␤-hydroxylation with inhibition constants (K i ) of approximately 2 and 0.1 M (Sutton et al., 1997). However, reversible inhibition may not sufficiently explain the observed drug interactions given that plasma concentrations of diltiazem and its metabolites are lower than their respective K i values. Time-dependent inactivation (TDI) was also observed in HLMs for both diltiazem (Jones et al., 1999;Dai et al., 2003) and MA (Mathew et al., 2000)...

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Section: Discussionsupporting

confidence: 70%

Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A

Zhao

Lee

Kunze³

2007

Drug Metab Dispos

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“…They suggested that an alteration of CsA metabolism by diltiazem was unlikely and that a decrease in apparent volume of distribution was a more probable explanation. Our findings with diltiazem also suggest that inhibition of CsA metabolism is unlikely given that peak diltiazem concentrations approximate to 1 FLM (Montamat & Abernethy, 1987).…”

Section: Resultssupporting

confidence: 54%

Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

Tjia

Back

Breckenridge

1989

Brit J Clinical Pharma

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The effects of four Ca2+ channel antagonists on the metabolism of cyclosporine (CsA) by human liver microsomes (n = 4) in vitro have been examined. Nicardipine produced marked inhibition of both M17 and M21 (IC50 = 7.0 microM) formation. In contrast nifedipine produced less than 20% inhibition of M17 and M21 even at the highest concentration examined (50 microM). Diltiazem data were comparable to those for nifedipine. Verapamil (50 microM) produced 30 and 28% inhibition of M17 and M21 formation, respectively. These findings give a basis to the increase in CsA blood concentrations seen in transplant patients who are also given nicardipine.

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“…The apparent k inact value (0.012 min -1 ) obtained for diltiazem using 0.2 mg/ml protein in the inactivation incubation underpredicted inactivation in hepatocytes ( Table 1 ) [34] and may lead to a conclusion that diltiazem is a remote time-dependent inactivator. Diltiazem is known to cause pharmacokinetic DDI in vivo [71,72] . Therefore, if M I is more potent inactivator, caution should be taken when rank ordering the TDI potential of NCEs based on parameters generated for parent inactivator under certain incubation conditions.…”

Section: Microsomal Time-dependent Inactivation Parameters Of Parent mentioning

confidence: 99%

The use of hepatocytes in evaluating time-dependent inactivation of P450in vivo

Zhao¹

2008

Expert Opinion on Drug Metabolism & Toxicology

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Factors that may impact prediction accuracy, such as nonspecific binding, metabolism of inactivator, active transport, and sequential inhibitory metabolites, can be assessed by performing 'in vitro-in vitro' correlation between microsomes and hepatocytes. Together with microsomal data and the aid of computer modeling and simulation, hepatocytes provide a powerful tool to optimize the integrated approaches aimed at quantitatively predicting TDI in vivo.

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N‐monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives.

Cited by 38 publications

References 12 publications

Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A

Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A

Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

The use of hepatocytes in evaluating time-dependent inactivation of P450in vivo

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