Pharmacokinetics of diltiazem and its metabolites in relation to <i>CYP2D6</i> genotype

Molden, Espen; Johansen, Per Wiik; Bøe, Grethe Helen; Bergan, Stein; Christensen, Hege; Rugstad, Hans Erik; Rootwelt, Helge; Reubsaet, Léon; Lehne, Gustav

doi:10.1067/mcp.2002.127396

Cited by 43 publications

(34 citation statements)

References 16 publications

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“…Considering that R-125528 itself could not be excreted into the bile or urine as an intact form, the -1 oxidation mediated by CYP2D6 was considered to be a crucial pathway for the elimination of R-125528 from the systemic circulation. CYP2D6 is one of the best known P450 isoforms that leads to large interindividual variations in drug concentration, drug response, therapeutic outcome, and/or toxicity because of its polymorphic nature (Brynne et al, 1998;Molden et al, 2002;Fux et al, 2005). The variability in CYP2D6 activity is mainly determined genetically, and 5 to 10% of Caucasians are reported to express a poor CYP2D6-metabolizing phenotype, resulting from the inheritance of two mutant null alleles (van der Weide and Steijns, 1999).…”

Section: Discussionmentioning

confidence: 99%

CYP2D6-Mediated Metabolism of a Novel Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor, Pactimibe, and Its Unique Plasma Metabolite, R-125528

Kotsuma¹,

Tokui²,

Ishizuka-Ozeki³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor. We conducted metabolic studies of pactimibe and its plasma metabolite, R-125528. Pactimibe had multiple metabolic pathways including indolin oxidation to form R-125528, -1 oxidation, N-dealkylation, and glucuronidation. Among them, the indolin oxidation and the -1 oxidation were dominant and were mainly catalyzed by CYP3A4 and CYP2D6, respectively. The intrinsic clearance (CL int ) values for these pathways in human hepatic microsomes were 0.63 and 0.76 l/min/mg-protein, respectively. On the other hand, the metabolic reaction for R-125528 was restricted. It was demonstrated that -1 oxidation was the only pathway that could eliminate R-125528 from the systemic circulation. Pactimibe sulfate (formerly named CS-505) ( Fig. 1) is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor used to treat hypercholesterolemia and atherosclerotic diseases (Nissen et al., 2006; Kitayama et al., 2006a,b,c). A number of acyl coenzyme A:cholesterol acyltransferase inhibitors have been evaluated by several investigators. However, because of poor pharmacokinetics (Peck et al., 1995), adverse effects such as adrenal toxicity (Vernetti et al., 1993;Reindel et al., 1994;Matsuo et al., 1996), diarrhea (Kashiwa et al., 1997), and hepatotoxicity (Ishi et al., 1994;Nakaya et al., 1994), and elusive efficacies in humans (Harris et al., 1990;Hainer et al., 1994;Tardif et al., 2004), none of these compounds have so far succeeded in clinical development.Pactimibe sulfate was selected as a clinical development candidate showing good oral absorbability and potent pharmacological effects in apolipoprotein E-deficient mice (Terasaka et al., 2007) and Watanabe heritable hyperlipidemic rabbits (Kitayama et al., 2006b) and without showing significant adrenal toxicity even in dogs, the most sensitive animal species. Pactimibe is a weak acidic compound and has several metabolic pathways including oxidation at the indolin ring, -1 oxidation at the octyl chain, N-dealkylation, and glucuronidation on the carboxylic acid. Kinetic studies using human liver microsomes revealed that indolin ring oxidation (formation of R-125528) and -1 oxidation (formation of M-1) were equally dominant and that glucuronidation and N-dealkylation were minor. In addition, none of the metabolites were estimated to be pharmacologically active in vitro.In vivo biotransformation studies in animals demonstrated that only pactimibe and R-125528, the oxidized form of the indolin ring in pactimibe, appeared in the plasma and that none of the other metabolites were observed. After oral administration of pactimibe sulfate at a dose of 1 mg/kg to rats, dogs, and monkeys, AUC R-125528 /AUC pactimibe ratios were calculated to be 3, 14, and 55%, respectively. On the other hand, pactimibe and R-125528 were not detected in the urine or bile but were excreted into the bile as further metabolized forms. R-125528 is quite a unique metabolite that has higher lipophilicity than the parent compound...

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Section: Discussionmentioning

confidence: 99%

CYP2D6-Mediated Metabolism of a Novel Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor, Pactimibe, and Its Unique Plasma Metabolite, R-125528

Kotsuma¹,

Tokui²,

Ishizuka-Ozeki³

et al. 2007

Drug Metab Dispos

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“…In humans, diltiazem is primarily metabolized to N-demethyldiltiazem, O-demethyldiltiazem, and deacetyldiltiazem by CYP3A4, CYP2D6, and esterase(s), respectively (Molden et al, 2002;Williams et al, 2002); however, the esterase(s) responsible for the deacetylation remained to be identified. Yeung et al (1990) reported that the AUC ratio of deacetyldiltiazem to diltiazem after an oral dose of diltiazem was much higher in rats (0.82) than in humans (0.12), suggesting the existence of species differences in the enzyme activity and/or substrate specificity of the esterase(s) involved in diltiazem deacetylation.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…1) (Yeung et al, 1990;Molden et al, 2002). N-demethylation and deacetylation are the major metabolic pathways, and the area under the curve (AUC) ratio of O-demethyldiltiazem, deacetyldiltiazem, and N-demethyldiltiazem reported in humans was 1:3.4:28, respectively (Molden et al, 2002). N-Demethyldiltiazem and deacetyldiltiazem have coronary vasodilation activity, with approximately one-fifth and one-half the potency of diltiazem, respectively (Yabana et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Species Differences in Tissue Diltiazem Deacetylation Identifies Ces2a as a Rat-Specific Diltiazem Deacetylase

2015

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Diltiazem, a calcium channel blocker, is mainly metabolized via demethylation or deacetylation in humans. Diltiazem demethylation is catalyzed by cytochrome P450 2D6 and 3A4. Although it was previously reported that the area under the curve ratio of deacetyldiltiazem to diltiazem after oral dosing with diltiazem in rats was sevenfold higher than in humans, the molecular mechanisms underlying this species difference remain to be clarified. In the present study, we compared the diltiazem deacetylase activity in liver, intestinal, renal, and pulmonary microsome preparations of human and experimental animal tissues to identify the specific deacetylase enzyme(s) involved in deacetylation. Diltiazem deacetylase activity was detected in rat liver and small intestine microsome preparations, but not in those from human, monkey, dog, and mouse tissues. Further purification of rat liver microsome (RLM) proteins identified four carboxylesterase (Ces) enzymes (Ces1d, Ces1e, Ces1f, and Ces2a) as potential candidate deacetylases. On the basis of their tissue distribution, the Ces2a enzyme was considered to be the enzyme that was responsible for diltiazem deacetylation. Furthermore, recombinant rat Ces2a expressed in Sf21 cells displayed efficient diltiazem deacetylase activity with similar Km values as RLM. In addition, the inhibitory characteristics of various chemical inhibitors were similar between recombinant rat Ces2a and RLM. In conclusion, we determined that only rat tissues were able to catalyze diltiazem deacetylation. The characterization of Ces enzymes in animal species, as undertaken in this study, will prove useful to predict the species-specific pharmacokinetics differences between the in vivo models used for drug development.

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“…CYP2D6 is one of the best known P450 isoforms and leads to large interindividual variations in drug concentration, drug response, therapeutic outcome, and/or toxicity because of its polymorphic nature (Brynne et al, 1998;Molden et al, 2002;Fux et al, 2005). Although CYP2D6 is a minor component (ϳ2%) of the total P450 content in the human liver, many drugs currently in clinical use are metabolized by CYP2D6, such as antiarrhythmics, antidepressants, antipsychotics, ␤-blockers, and analgesics (Jones et al, 1997).…”

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confidence: 99%

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

Kotsuma

Hanzawa²,

Iwata³

et al. 2008

Drug Metab Dispos

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Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype

Cited by 43 publications

References 16 publications

CYP2D6-Mediated Metabolism of a Novel Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor, Pactimibe, and Its Unique Plasma Metabolite, R-125528

CYP2D6-Mediated Metabolism of a Novel Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor, Pactimibe, and Its Unique Plasma Metabolite, R-125528

Characterization of Species Differences in Tissue Diltiazem Deacetylation Identifies Ces2a as a Rat-Specific Diltiazem Deacetylase

Novel Binding Mode of the Acidic CYP2D6 Substrates Pactimibe and Its Metabolite R-125528

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