Quantitative Analyses Of Pramipexole And Domperidone In Human Plasma

1. Quantitative analysis of pramipexole in human plasma and their applicationsBACKGROUND Pramipexole is an orally active, non-ergoline, dopamine agonist used for the treatment of Parkinson’s disease. The absorption of pramipexole after an oral dose is greater than90%and, of the amount that reaches the systemic circulation, approximately90%is excreted in the urine as unchanged drug. Therapy with pramipexole tablets is initiated at a low dose (0.125mg) and the Cmax of pramipexole at0.125mg is less than0.61ng·mL-1.OBJECTIVE To develop and validate a high sensitive, rapid and specific liquid chromatographic-tandem mass spectrometric method for determination of pramipexole in human plasma and application to the clinical pharmacokinetics of low dose. METHOD The plasma sample was extracted with ethyl ether-dichlormethane (3:2, v/v), then separated on a Venusil ASB-C18(150mmX4.6mm I.D.,5μm) column using acetonitrile-10mmol-L"1ammonium acetate-formic acid (60:40:0.1, v/v/v) as the mobile phase. A tandem mass spectrometer equipped with electrospray ionization source was used as the detector and operated in the positive ion mode. Quantitation was performed using selective reaction monitoring (SRM) of the transitions of m/z212â†'m/z (111+126+153) and m/z243â†'m/z210for pramipexole and the internal standard huperzine A, respectively.RESULTS The linear calibration curves were obtained in the concentration range of5.92-740pg-mL’1. The lower limit of quantification was5.92pg-mL’1. The intra-day and inter-day relative standard deviation over the entire concentration range was less than9.7%. The accuracy was in the range of-2.5%to0.6%in terms of relative error. The method was successfully applied to a pharmacokinetic study of pramipexole dihydrochloride monohydrate tablets containing0.125mg or0.25mg in healthy volunteers. After single oral doses of0.125and0.25mg pramipexole to healthy volunteers, respectively, the pharmacokinetic parameters (AUC and Cmax) of pramipexole were increased inpro dose. The main pharmacokinetic parameters for pramipexole exhibited significant individual differences.CONCLUSION Three SRM transitions are selected in the quantification of pramipexole, which improve the sensitivity of the method significantly, and the method is proved to be suitable for the determination of pramipexole in human plasma.2. Quantitative analysis of domperidone in human plasma and their applicationsBACKGROUND Domperidone is a peripheral dopamine D2receptor antagonist that does not readily enter the central nervous system, for the treatment of postprandial dyspepsia and prevention of gastrointestinal symptoms associated with anti-Parkinson agents’use. Extensive first-pass hepatic and gut wall metabolism results to low bioavailability of domperidone (13%-17%).OBJECTIVE To develop and validate a sensitive, rapid and specific liquid chromatographic-tandem mass spectrometric method for determination of domperidone in human plasma and application to the clinical pharmacokinetics of low dose.METHOD The analyte and internal standard (IS; pioglitazone) were isolated from plasma samples by protein precipitation with acetonitrile, then separated on a Zorbax SB-C8(150mm×4.6mm LD.,5μm) column using acetonitrile-10mmol·L-1ammonium acetate (60:40, v/v) as the mobile phase. A tandem mass spectrometer equipped with Atmospheric Pressure Chemical Ionization source was used as the detector and operated in the positive ion mode. Quantitation was performed using selective reaction monitoring (SRM) of the transitions of m/z426â†'m/z175and m/z357â†'m/z (134+119) for domperidone and the internal standard pioglitazone, respectively.RESULTS The linear calibration curves were obtained in the concentration range of0.100-50.0ng·mL-1. The lower limit of quantification was0.100ng·mL-1. The intra-day and inter-day relative standard deviation over the entire concentration range was less than7.3%. The accuracy was in the range of-1.6%to-0.1%in terms of relative error. Following a single oral dose of10mg domperidone test formulation,90%confidence interval for AUC0â†'30h and Cmax were93.5%-108%and82.3%-115%, respectively. Thus the test formulation of domperidone was considered bioequivalent to the reference formulation according to both the rate and the extent of absorption and confirm marked intra-and inter-individual variations in the pharmacokinetics.CONCLUSION The validated liquid chromatographic-tandem mass spectrometric methods is sensitive, selective, rapid and suitable for evaluating the clinical pharmacokinetics of domperidone in humans.