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Doctoral Thesis
DOI
https://doi.org/10.11606/T.9.2003.tde-22022022-123910
Document
Author
Full name
Paula Macedo Cerqueira
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2003
Supervisor
Committee
Lanchote, Vera Lucia (President)
Bonato, Pierina Sueli
Coelho, Eduardo Barbosa
Pinto, Luis Felipe Ribeiro
Santos, Silvia Regina Cavani Jorge
Title in Portuguese
Estereosseletividade no metabolismo do metoprolol em pacientes hipertensos portadores ou não de insuficiência renal crônica
Keywords in Portuguese
CYP2D6
Enantiômero
Farmacocinética
Hipertensão
Insuficiência renal crônica
Metoprolol
Pacientes
Abstract in Portuguese
Neste estudo investiga-se a influência da insuficiência renal crônica no metabolismo estereosseletivo do metoprolol administrado sob forma racêmica, em regime de doses múltiplas p.o.. Foram investigados 15 pacientes, de ambos os sexos, portadores de hipertensão arterial associada ou não a insuficiência renal crônica (IRC), divididos em dois grupos de acordo com o clearance da creatinina. Os pacientes foram fenotipados empregando a debrisoquina como fármaco marcador (CYP2D6), de acordo com a razão metabólica debrisoquina/ 4-hidroxidebrisoquina na urina de 0-8 h. Os pacientes foram tratados com placebo, 50, 100 e 200 mg de tartarato de metoprolol (Seloken®, Astra, São Paulo, Brasil) a cada 24 horas durante 7 dias para cada tratamento. No final de cada semana foi realizada a monitorização ambulatorial da pressão arterial e colhida uma amostra de sangue para dosagem de noradrenalina. No sétimo dia da administração de 200 mg foram colhidas amostras seriadas de sangue e amostras de urina no intervalo de 0-36 h. Os enantiômeros (R)-(+) e (S)-(-)-metoprolol e os 4 isômeros do α-hidroximetoprolol (coluna Chiralpak® AD) e os enantiômeros do ácido O-desmetilmetoprolóico (coluna Chiralcel® OD-R) foram analisados em plasma e urina por cromatografia líquida de alta eficiência empregando detecção por fluorescência (λexc= 229 nm; λem= 298 nm). Não houve alteração da concentração plasmática de noradrenalina assim como da pressão arterial sistólica e diastólica nas diferentes fases do tratamento. Em ambos os grupos a freqüência cardíaca foi reduzida após administração de 200 mg de metoprolol. Os parâmetros farmacocinéticos apresentaram diferença significativa (p<0,05, teste Wilcoxon) entre os enantiômeros (R)-(+)- e (S)-(-)-metoprolol nos grupos Controle e IRC para os pacientes com fenótipo de metabolizadores rápidos da debrisoquina, resultando em acúmulo plasmático do eutômero (S)-(-)-. Houve favorecimento na formação do novo centro quiral 1R-α-OHM em ambos enantiômeros do metoprolol, resultando em razões 1R/1S≅ 2,5 nos dois grupos. Houve um favorecimento na formação do (R)-(+)-AODM nos dois grupos, justificando o acúmulo plasmático do (S)-(-)-metoprolol. Ao compararmos os parâmetros farmacocinéticos entre os grupos Controle e IRC (teste Mann-Whitney) observamos que a farmacocinética do metoprolol não foi alterada apesar do acúmulo plasmático de todos os isômeros do α-hidroximetoprolol e ácido O-desmetilmetoprolóico. Os dois pacientes fenotipados como metabolizadores lentos da debrisoquina não formaram α- hidroximetoprolol e houve um favorecimento na formação do (S)-(-)-ácido O-desmetilmetoprolóico, com conseqüente acúmulo plasmático do (R)-(+)-metoprolol. As diferenças entre os grupos Controle e IRC na formação dos metabólitos do metoprolol sugerem que a IRC não induz o CYP2D6 mas induz a atividade do outro sistema enzimático responsável pela formação do ácido O-desmetilmetoprolóico.
Title in English
Stereoselectivity in metoprolol metabolism in hypertensive patients with and without chronic renal failure
Keywords in English
Chronic renal failure
CYP2D6
Enantiomers
Hypertension
Metoprolol
Patients
Pharmacokinetics
Abstract in English
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.
 
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Publishing Date
2022-02-22
 
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