title: Stereoselective analysis of labetalol in human plasma by LC-MS/MS: application to pharmacokinetics.
abstract: Labetalol is clinically available as a mixture of two racemates (four stereoisomers). The stereoisomer (R,R) has as main activity the beta1-antagonism and the stereoisomer (S,R) is highly selective for the alpha1 adrenoceptor and is responsible for most of the alpha-blocker activity. In the present investigation, a method for the analysis of labetalol stereoisomers in human plasma was developed and applied to pharmacokinetic studies. Plasma samples (0.5 ml) were extracted with methyl tert-butyl ether at pH 9.5. The four labetalol stereoisomers were analyzed by LC-MS/MS on a Chirobiotic V column using a mobile phase consisting of methanol, acetic acid, and diethylamine, with a recovery of more than 90% for all four. The quantitation limit was 0.5 ng/ml and linearity was observed at 250 ng/ml plasma for each stereoisomer. Studies of precision and accuracy presented coefficients of variation and percentage inaccuracy of less than 15%, indicating that the method is precise and accurate. The method was applied to the study of the kinetic disposition of labetalol over a period of 12 h after oral administration of a single 100 mg dose to a hypertensive pregnant woman. The clinical study revealed stereoselectivity in the pharmacokinetics of labetalol, with a lower plasma proportion for the active stereoisomers (R,R)-labetalol and (S,R)-labetalol. The stereoselectivity observed after oral administration is due to the hepatic metabolism and the first pass effect, with an AUC(R,R)/AUC(S,S) ratio of 0.5.
authors.affiliation: Department of Clinical, Toxicologic, and Bromatologic Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Teresa Maria De Jesus Ponte
authors.initials: TM
authors.lastname: Carvalho
authors.forename: Ricardo De Carvalho
authors.initials: Rde C
authors.lastname: Cavalli
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Sérgio Pereira
authors.initials: SP
authors.lastname: Da Cunha
authors.forename: Claúdia De Oliveira
authors.initials: Cde O
authors.lastname: Baraldi
authors.forename: Vera Lúcia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000959:Antihypertensive Agents / Q000097:blood / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007741:Labetalol / Q000097:blood / Q000737:chemistry*; D015394:Molecular Structure; D010599:Pharmacokinetics; D011247:Pregnancy; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: D000959:Antihypertensive Agents; D007741:Labetalol