Metoprolol oxidation polymorphism in Brazilian elderly cardiac patients Daniel Valente Neves a , Vera Lucia Lanchote a , Luiz de Souza b , Miyeko Hayashida c , Maria Sueli Nogueira c , Natália Valadares de Moraes a and Evandro José Cesarino a * a School of Pharmaceutical Sciences of Ribeirão Preto, b School of Medicine of Ribeirão Preto, Department of Child Care and Pediatrics, and c College of Nursing, Department of General and Specialized Nursing, University of São Paulo, Ribeirão Preto, São Paulo, Brazil Keywords CYP2D6; elderly; metoprolol; polymorphism; phenotype *Correspondence Evandro José Cesarino, University of Sao Paulo, School of Pharmaceutical Sciences of Ribeirão Preto, Department of Clinical Analy- sis, Toxicological and Bromatological, Avenue of Café s/n, Campus of University of Sao Paulo, Ribeirão Preto, São Paulo ZIP 14040- 903, Brazil. E-mail: cesarino@fcfrp.usp.br e-mail address: Daniel Valente Neves: danvn83@fcfrp.usp.br; Vera Lucia Lanchote: lanchote@fcfrp.usp.br; Luiz de Souza: ldsouza@fmrp.usp.br; Miyeko Hayashida: miyeko@eerp.usp.br; Maria Sueli Nogueira: msnog@eerp.usp.br; Natália Valadares de Moraes: nataliavaladaresdemoraes@gmail.com Received November 16, 2012 Accepted June 15, 2013 doi: 10.1111/jphp.12109 Abstract Objectives The purpose of this study was to phenotype the CYP2D6 in elderly with heart disease classified as extensive metabolizer or poor metabolizers (PM) of metoprolol, develop and validate the method of analysis of metoprolol tartrate and its metabolite in urine using HPLC, and identify potential correlations between anthropometric factors with metabolic ratios of metoprolol/a-OH meto- prolol in urine. Methods The sample was composed of 130 elderly individuals with a previously identified type of heart condition, with normal renal and hepatic functions. The urine of all the patients were collected 0–8 h after the administration of a pill of 100 mg of metoprolol to determine concentrations of metoprolol and a-hydroxymetoprolol. Those patients presenting a metabolic ratio greater than 12.6 were phenotyped as PM. Key findings The median age of patients was 71.0 years, with a minimum of 60 and maximum of 93 years old. Three patients (2.3%) were phenotyped as PM of metoprolol different from the rate (7–10%) of PM existing in the Caucasian population. Conclusions Most of the studied individuals were women, and the proportion of elderly with heart disease classified as PM was smaller than what is usually found among Caucasian populations. Introduction CYP2D6 is involved in the oxidative metabolism of approximately 25% of all the prescribed drugs, and it is characterized by a high rate of interindividual and interethnic variability. [1] Individuals are classified into four phenotypes according to the CYP2D6 activity: ultra-rapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). [2,3] Because of this polymorphism, the drug may present a difference of 30–40 times in clearance. Hence, the drug’s plasma concentration may be outside the thera- peutic range and either cause adverse effects or therapeutic failure. [1] Physiological changes and cardiovascular diseases in elderly patients can affect the pharmacokinetics of certain drugs. Prescott et al. reported that a half-life of lignocaine was three times greater in patients with acute myocardial infarction (AMI) when compared with healthy individu- als. [4] Van Griensven et al. showed an increase in the plasma concentrations of saruplase in patients with AMI that was mainly due to the decreased hepatic blood flow, which affects the metabolism of this drug. [5] Hanson et al. also demonstrated that patients with chronic heart failure New York Heart Association (NYHA) class III and IV, treated with a single dose of 50 mg of hydralazin, presented higher area under the curve (AUC) values compared with patients with essential hypertension. [6] Orlando et al. in turn reported a significant increase in AUC and Cmax, and a decrease in CL/F in fluvoxamine in healthy older adults in comparison with healthy younger adults, although no sig- nificant differences were found in AUC, Cmax and CL/F And Pharmacology Journal of Pharmacy Research Paper © 2013 University of Sao Paulo. JPP © 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 65, pp. 1347–1353 1347 Downloaded from https://academic.oup.com/jpp/article/65/9/1347/6132947 by guest on 08 April 2023