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      Olanzapine-Associated Rhabdomyolysis: A Case Report

      case-report
      1 , , 2 , 3
      ,
      Cureus
      Cureus
      pharmacogenetics, olanzapine, creatine kinase, rhabdomyolysis, personalized medicine, pgx2

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          Abstract

          This paper presents the case of a 20-year-old patient with a suspected diagnosis of paranoid schizophrenia. He was prescribed oral olanzapine at a dose of 10 mg per day, and the treatment was associated with rhabdomyolysis (serum creatine kinase = 9,725 U/L on day four of the therapy). On suspicion of its contribution to rhabdomyolysis, olanzapine was immediately withdrawn. Pharmacogenetic testing demonstrated that the patient’s CYP2D6 genotype was *4/*4 (1846G>A, rs3892097). Based on these results, the patient was switched to trifluoperazine, a medication that is not metabolized by the CYP2D6 isoenzyme. Subsequently, the patient recovered well and was discharged without any nephrological sequelae. The presented case demonstrates that pharmacogenetic‐guided personalization of treatment may allow selecting the best medication and determining the right dosage, resulting in the reduced risk of adverse drug reactions and pharmacoresistance.

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            Metabolism of atypical antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactions.

            The involvement of cytochrome P450 (CYP) enzymes in the metabolism of the atypical (second-generation) antipsychotics clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and amisulpride is reviewed, and the possible relevance of this metabolism to drug-drug interactions is discussed. Clozapine is metabolized primarily by CYP1A2, with additional contributions by CYP2C19, CYP2D6 and CYP3A4. Risperidone is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4; the 9-hydroxy metabolite of risperidone (paliperidone) is now marketed as an antipsychotic in its own right. Olanzapine is metabolized primarily by direct glucuronidation and CYP1A2 and to a lesser extent by CYP2D6 and CYP3A4. Quetiapine is metabolized by CYP3A4, as is ziprasidone, although in the latter case aldehyde oxidase is the enzyme responsible for most of the metabolism. CYP2D6 and CYP3A4 are important in the metabolism of aripiprazole, and CYP-catalyzed metabolism of paliperidone and amisulpride appears to be minor. At the usual clinical doses, these drugs appear to not generally affect markedly the metabolism of other coadministered medications. However, as indicated above, several of atypical antipsychotics are metabolized by CYP enzymes, and physicians should be aware of coadministered drugs that may inhibit or induce these CYP enzymes; examples of such possible interactions are presented in this review.
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              Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe

              CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of all medications. Importantly, the corresponding genes are highly polymorphic and these genetic differences contribute to interindividual and interethnic differences in drug pharmacokinetics, response, and toxicity. In this study we systematically analyzed the frequency distribution of clinically relevant CYP2C19 and CYP2D6 alleles across Europe based on data from 82,791 healthy individuals extracted from 79 original publications and, for the first time, provide allele confidence intervals for the general population. We found that frequencies of CYP2D6 gene duplications showed a clear South-East to North-West gradient ranging from <1% in Sweden and Denmark to 6% in Greece and Turkey. In contrast, an inverse distribution was observed for the loss-of-function alleles CYP2D6*4 and CYP2D6*5. Similarly, frequencies of the inactive CYP2C19*2 allele were graded from North-West to South-East Europe. In important contrast to previous work we found that the increased activity allele CYP2C19*17 was most prevalent in Central Europe (25–33%) with lower prevalence in Mediterranean-South Europeans (11–24%). In summary, we provide a detailed European map of common CYP2C19 and CYP2D6 variants and find that frequencies of the most clinically relevant alleles are geographically graded reflective of Europe’s migratory history. These findings emphasize the importance of generating pharmacogenomic data sets with high spatial resolution to improve precision public health across Europe.
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                Author and article information

                Journal
                Cureus
                Cureus
                2168-8184
                Cureus
                Cureus (Palo Alto (CA) )
                2168-8184
                8 January 2021
                January 2021
                : 13
                : 1
                : e12568
                Affiliations
                [1 ] Department No. 2, Moscow Research and Practical Centre on Addictions, Moscow, RUS
                [2 ] Laboratory of Genetics and Fundamental Studies, Moscow Research and Practical Centre on Addictions, Moscow, RUS
                [3 ] Clinical Pharmacology and Therapy Department, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, RUS
                Author notes
                Valentin Y. Skryabin sardonios@ 123456yandex.ru
                Article
                10.7759/cureus.12568
                7863024
                061ea501-df24-4529-a542-2c2f8dd82d68
                Copyright © 2021, Skryabin et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 January 2021
                Categories
                Psychiatry

                pharmacogenetics,olanzapine,creatine kinase,rhabdomyolysis,personalized medicine,pgx2

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