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      Effect of N-methyl deuteration on metabolism and pharmacokinetics of enzalutamide

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          The replacement of hydrogen with deuterium invokes a kinetic isotope effect. Thus, this method is an attractive way to slow down the metabolic rate and modulate pharmacokinetics.


          Enzalutamide (ENT) acts as a competitive inhibitor of the androgen receptor and has been approved for the treatment of metastatic castration-resistant prostate cancer by the US Food and Drug Administration in 2012. To attenuate the N-demethylation pathway, hydrogen atoms of the N–CH 3 moiety were replaced by the relatively stable isotope deuterium, which showed similar pharmacological activities but exhibited favorable pharmacokinetic properties.


          We estimated in vitro and in vivo pharmacokinetic parameters for ENT and its deuterated analog (d 3-ENT). For in vitro studies, intrinsic primary isotope effects ( K H/ K D) were determined by the ratio of intrinsic clearance (CL int) obtained for ENT and d 3-ENT. The CL int values were obtained by the substrate depletion method. For in vivo studies, ENT and d 3-ENT were orally given to male Sprague Dawley rats separately and simultaneously to assess the disposition and metabolism of them. We also investigated the main metabolic pathway of ENT by comparing the rate of oxidation and hydrolysis in vitro.


          The in vitro CL int (maximum velocity/Michaelis constant [ V max/ K m]) of d 3-ENT in rat and human liver microsomes were 49.7% and 72.9% lower than those of the non-deuterated compound, corresponding to the K H/ K D value of ~2. The maximum observed plasma concentration, C max, and area under the plasma concentration -time curve from time zero to the last measurable sampling time point (AUC 0–t) were 35% and 102% higher than those of ENT when orally administered to rats (10 mg/kg). The exposure of the N-demethyl metabolite M2 was eightfold lower, whereas that of the amide hydrolysis metabolite M1 and other minor metabolites was unchanged. The observed hydrolysis rate of M2 was at least ten times higher than that of ENT and d 3-ENT in rat plasma.


          ENT was mainly metabolized through the “parent→M2→M1” pathway based on in vitro and in vivo elimination behavior. The observed in vitro deuterium isotope effect translated into increased exposure of the deuterated analog in rats. Once the carbon–hydrogen was replaced with carbon–deuterium (C–D) bonds, the major metabolic pathway was retarded because of the relatively stable C–D bonds. The systemic exposure to d 3-ENT can increase in humans, so the dose requirements can be reduced appropriately.

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          Most cited references 26

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          Heavy drugs draw heavy interest from pharma backers.

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            Clinical Pharmacokinetic Studies of Enzalutamide

            Background and Objectives Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide. Methods Results are reported from five clinical studies. Results In a dose-escalation study (n = 140), enzalutamide half-life was 5.8 days, steady state was achieved by day 28, accumulation was 8.3-fold, exposure was approximately dose proportional from 30–360 mg/day, and intersubject variability was ≤30 %. In a mass balance study (n = 6), enzalutamide was primarily eliminated by hepatic metabolism. Renal excretion was an insignificant elimination pathway for enzalutamide and N-desmethyl enzalutamide. In a food-effect study (n = 60), food did not have a meaningful effect on area under the plasma concentration–time curve (AUC) of enzalutamide or N-desmethyl enzalutamide, and in an hepatic impairment study, AUC of the sum of enzalutamide plus N-desmethyl enzalutamide was similar in men with mild (n = 6) or moderate (n = 8) impairment (Child–Pugh Class A and B) versus men with normal hepatic function (n = 14). In a phase III trial, an exposure-response analysis of steady-state predose (trough) concentrations (C trough) versus overall survival (n = 1103) showed that active treatment C trough quartiles for 160 mg/day were uniformly beneficial relative to placebo, and no threshold of C trough was associated with a statistically significant better response. Conclusions Enzalutamide has predictable pharmacokinetics, with low intersubject variability. Similar efficacy was observed in patients across the concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day. Electronic supplementary material The online version of this article (doi:10.1007/s40262-015-0271-5) contains supplementary material, which is available to authorized users.
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              Deuterium isotope effects on drug pharmacokinetics. I. System-dependent effects of specific deuteration with aldehyde oxidase cleared drugs.

              The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drug's metabolic clearance, and differences in systemic clearance mechanisms are critically important for the pharmacokinetic application of deuterium isotope effects. Ex vivo methods to project the in vivo outcome using deuterated carbazeran and zoniporide with hepatic systems demonstrate the importance of establishing the extent to which other metabolic enzymes contribute to the metabolic clearance mechanism. Differences in pharmacokinetic outcomes in guinea pig and rat, with the same metabolic clearance mechanism, show how species differences in the systemic clearance mechanism can affect the in vivo outcome. Overall, to gain from the application of deuteration as a strategy to alter drug pharmacokinetics, these studies demonstrate the importance of understanding the systemic clearance mechanism and knowing the identity of the metabolic enzymes involved, the extent to which they contribute to metabolic clearance, and the extent to which metabolism contributes to the systemic clearance.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                07 July 2016
                : 10
                : 2181-2191
                [1 ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai
                [2 ]University of Chinese Academy of Sciences, Beijing
                [3 ]Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences
                [4 ]Hinova Pharmaceuticals Inc, Chengdu, People’s Republic of China
                Author notes
                Correspondence: Dafang Zhong, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, People’s Republic of China, Tel/fax +86 21 5080 0738, Email dfzhong@ 123456simm.ac.cn

                These authors contributed equally to this work

                © 2016 Jiang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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