Stereoselectivity in metoprolol metabolism in hypertensive patients with and without chronic renal failure

Author(s)

Paula Macedo Cerqueira

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2003-04-09

Examining board members

Vera Lucia Lanchote; Pierina Sueli Bonato; Eduardo Barbosa Coelho; Luis Felipe Ribeiro Pinto; Silvia Regina Cavani Jorge Santos

• Advisor: Vera Lucia Lanchote

Abstract

In the present study we investigated the influence of chronic renal failure (CRF) in the stereoselective metabolism of metoprolol administered in the racemic form in a p.o. multiple-dose regimen. The study was conducted on 15 patients of both sexes with essential hypertension, divided into two groups according to their creatinine clearances. Toe patients were phenotyped using debrisoquine as probe drug (CYP2D6) according to the urine ratios debrisoquine to 4-hydroxydebrisoquine. Toe patients were treated with placebo, 50, 100 and 200 mg of metoprolol tartrate (Seloken®, Astra, Brazil) every 24 h for 7 days each treatment. A blood sample was collected and the ambulatory blood pressure was monitored in the end of each week. Serial blood samples and urine were collected during 36 h after seven days of 200 mg metoprolol administration. Toe plasma and urine concentrations of metoprolol and α-hydroxymetoprolol (Chiralpak® AD column) and metoprolol acidic metabolite isomers (Chiralcel® OD-R column) were determined by HPLC using fluorescence detection (λexc= 229 nm; λem= 298 nm). Plasmatic noradrenaline concentrations and systolic and diastolic blood pressure did not change in the different treatment phases. Heart beat was reduced in both groups after 200 mg metoprolol administration: Pharmacokinetic parameters were statistically different between (S)-(-)- and (R)-(+)-metoprolol in the control and chronic renal failure groups for the patients phenotyped as debrisoquine extensive metabolizers, resulting in the plasmatic accumulation of the eutomer (S)-(-)-. The formation of the new chiral centre 1R-α-hydroxymetoprolol was favoured for both metoprolol enantiomers, resulting in ratios 1R/1S≅ 2.5 in both groups. The formation of (R)-(+)-metoprolol acidic metabolite was favoured in both groups, supporting the plasmatic accumulation of (S)-(-)-metoprolol. Comparing the pharmacokinetics parameters between the control and CRF groups (Mann-Whitney test), we can observe that metoprolol pharmacokinetics was not altered despite the plasmatic accumulation of all the α-hydroxymetoprolol and metoprolol acidic metabolite isomers. The two patients phenotyped as debrisoquine poor metabolizers did not form α-hydroxymetoprolol and the formation of (S)-(-)- metoprolol acidic metabolite was favoured, resulting in the plasmatic accumulation of (R)-(+)-metoprolol. The differences observed between the Control and CRF groups suggest that the chronic renal failure does not induce CYP2D6 but induces the activity of the other enzymatic system responsible for the formation of metoprolol acidic metabolite. (AU)