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Doctoral Thesis
DOI
10.11606/T.60.2009.tde-13072009-151617
Document
Author
Full name
Teresa Maria de Jesus Ponte Carvalho
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2009
Supervisor
Committee
Lanchote, Vera Lucia (President)
Duarte, Geraldo
Bonato, Pierina Sueli
Cavalli, Ricardo de Carvalho
Cesarino, Evandro José
Title in Portuguese
Influência do diabetes mellitus gestacional na disposição cinética e metabolismo estereosseletivos do labetalol em pacientes com hipertensão arterial
Keywords in Portuguese
diabetes mellitus gestacional
estereoisômeros
farmacocinética
gravidez
hipertensão arterial
labetalol
metabolismo
Abstract in Portuguese
O labetalol, um anti-hipertensivo considerado seguro para uso em gestantes, está disponível na clínica como mistura de dois racematos (quatro estereoisômeros), sendo o isômero (R,R) antagonista e o (S,R) responsável pela atividade bloqueadora. O estudo investiga a influência do diabetes mellitus gestacional (DMG) na disposição cinética e no metabolismo estereosseletivos do labetalol administrado por via endovenosa ou oral. Foram investigadas 30 gestantes hipertensas distribuídas em 04 grupos: não diabéticas tratadas com dose única de 40 mg de cloridrato de labetalol endovenoso (grupo EVH, n=8) ou 100 mg de cloridrato de labetalol via oral (grupo VOH, n=9) e diabéticas tratadas com 40 mg de cloridrato de labetalol endovenoso (grupo EVD, n=6) ou 100 mg de cloridrato de labetalol via oral (grupo VOD, n=7). As amostras seriadas de sangue foram coletadas até 12 h (via oral) ou 15 h (via endovenosa) após a administração do cloridrato de labetalol. Os estereoisômeros do labetalol em plasma foram analisados em coluna de fase quiral Chirobiotic V empregando LC-MS-MS. Os parâmetros farmacocinéticos do labetalol inalterado e labetalol glicuronídeo foram calculados com auxílio do programa WinNonlin e avaliados empregando os testes de Mann-Whitney e Friedman com pós-teste de Dunn (p<0,05). A farmacocinética do labetalol não é estereosseletiva em gestantes diabéticas e não diabéticas tratadas com o fármaco por via endovenosa. No entanto, a administração oral de labetalol resulta em menores valores de área sob a curva concentração plasmática versus tempo (AUC) para o isômero ativo (R,R)-labetalol tanto em gestantes diabéticas (60,9 vs 162,7 vs 157,9 vs 114,6 ng.h/mL, respectivamente para (R,R,); (SR); (S,S,) e (R,S)) quanto não diabéticas (45,6 vs 84,2 vs 89,4 vs 78,3 ng.h/mL, respectivamente para (R,R,); (SR); (S,S,) e (R,S)). O DMG resulta em alterações na disposição cinética dos estereoisômeros do labetalol na administração oral. Os valores de AUC do isômero inativo (S,S)-labetalol (157,9 vs 89,4 ng.h/mL) e para o isômero -bloqueador (S,R)-labetalol (162.7 vs 84.2 ng.h/mL) são maiores (p<0,05) nas gestantes diabéticas do que nas gestantes não diabéticas. As gestantes diabéticas também mostram maior biodisponibilidade oral do isômero (S,R)-labetalol (54,7 vs 24,0 %) explicada pela reduzida eliminação pré-sistêmica conseqüente da menor capacidade de conjugação com o ácido glicurônico (68,4 vs 77,9 %). Os valores de AUC do isômero (S,R) aproximadamente 100 % maiores nas gestantess diabéticas tratadas com o fármaco por via oral (162,7 vs 84,2 ng.h/mL) pode ter relevância clínica considerando a atividade -bloqueadora do referido isômero.
Title in English
Influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol in patients with arterial hypertension,
Keywords in English
gestational diabetes mellitus
hypertension
labetalol
pharmacokinetics
pregnancy
stereoisomers
Abstract in English
Labetalol, a hypertensive agent considered to be safe for use by pregnant women, is clinically available as a mixture of two racemates, with the (R,R) isomer being a antagonist and the (S,R) isomer being responsible for the blocking activity. The study investigated the influence of gestational diabetes mellitus (GDM) on the kinetic disposition and stereoselective metabolism of labetalol administered by the intravenous or oral route. Thirty hypertensive pregnant women were divided into 4 groups: non-diabetic women treated with a single 40 mg dose of intravenous labetalol hydrochloride (IVH group, n=8) or with 100 mg labetalol hydrochloride by the oral route (OH group, n=9) and diabetic women treated with 40 mg intravenous labetalol hydrochloride (IVD), n=6) or with 100 mg labetalol hydrochloride by the oral route (OD, n=7). Serial blood samples were collected up to 12 h (oral route) or 15 h (intravenous route) after the administration of labetalol hydrochloride. The labetalol stereoisomers in plasma were analyzed with a chiral phase Chirobiotic V column by LC-MS-MS. The pharmacokinetic parameters of unchanged labetalol and glucuronide labetalol were calculated using the WinNolin software and analyzed by the Mann-Whitney and Friedman tests followed by the Dunn test (p<0.05). The pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women treated with the drug by the intravenous route. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the active isomer (R,R)-labetalol both in diabetic (60.9 vs 162.7 vs 157.9 vs 114.6 ng.h/mL, respectively for (R,R,), (SR), (S,S,) and (R,S)) and non-diabetic pregnant women (45.6 vs 84.2 vs 89.4 vs 78.3 ng.h/mL, respectively for (R,R,), (SR), (S,S,) and (R,S)). GDM involves changes in the kinetic disposition of the stereoisomers of labetalol when administered by the oral route. The AUC values for the inactive (S,S)-labetalol (157.9 vs 89.4 ng.h/mL) and for the -blocking (S,R) isomer (162.7 vs 84.2 ng.h/mL) were higher (p<0.05) for the diabetic than the non-diabetic pregnant women. The diabetic pregnant women showed greater oral bioavailability of the (S,R)-labetalol isomer (54.7 vs 24.0 %), explained by the reduced pre-systemic elimination due to the lower capacity for conjugation with glucuronic acid (68.4 vs 77.9 %). The approximately 100 % higher AUC values of the (S,R) isomer for the diabetic pregnant women treated with the drug by the oral route may be of clinical relevance in view of the -blocking activity of the isomer in question.
 
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Publishing Date
2009-09-29
 
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