Abstract
Sensitive and selective analytical method is required for the estimation of lovastatin in human plasma as lovastatin has been reported to have high intra-subject variability and is converted to its active metabolite lovastatin hydroxy acid in in vitro system and vice versa. If this inter-conversion is not restricted, it could lead to pseudo estimation of lovastatin in human plasma. A specific, sensitive, and reproducible high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for determination of lovastatin in human plasma, using lovastatin-d3 as an internal standard. Lovastatin and lovastatin-d3 were extracted from human plasma using solid phase extraction, separated on Luna C18 (2)100A (100 × 4.6 mm, 5 μm) column with mobile phase consisting of acetonitrile and 2 mM ammonium acetate buffer (pH 3.6) in the ratio of 90:10, v/v. Quantification was achieved by monitoring transitions of m/z 422.1 → 285.4 for lovastatin and 425.4 → 285.4 for lovastatin-d3 in multiple reaction monitoring, using turbo ion source in positive polarity. No matrix effect was observed within the linearity range of 0.121–35.637 ng/mL (r > 0.99). The degree of matrix effect for lovastatin was determined as 2.74 %, and it had no impact on incurred samples analysis with run time of 4.5 min. The intra- and inter-day precision values were within 11.38 and 8.62 % respectively, for lovastatin at the lower limit of quantification level. Stability data indicated that lovastatin is stable under various handling conditions and with insignificant inter-conversion between lovastatin and lovastatin hydroxy acid. The method was successfully applied for the bioequivalence study of lovastatin after oral administration of 40 mg tablet in healthy volunteer.
Highlights
Sensitive and selective analytical method is required for the estimation of lovastatin in human plasma as lovastatin has been reported to have high intra-subject variability and is converted to its active metabolite lovastatin hydroxy acid in in vitro system and vice versa
The kinetics of in vitro inter-conversion between lactone and its hydroxy acid form has been reported by Kearney et al (1993) and Won (1994), its application for the estimation of lovastatin in the bioequivalence study has not been reported till date
In order to develop a method with the desired limit of quantification (LOQ), it was necessary to use MS-MS detection
Summary
Sensitive and selective analytical method is required for the estimation of lovastatin in human plasma as lovastatin has been reported to have high intra-subject variability and is converted to its active metabolite lovastatin hydroxy acid in in vitro system and vice versa. If this inter-conversion is not restricted, it could lead to pseudo estimation of lovastatin in human plasma. Lovastatin is a cholesterol-lowering agent, used in the treatment of hypercholesterolemia It is a lactone, which hydrolyzes readily in vivo to its β-hydroxy acid form, an inhibitor of 3-hydroxy-3-methylgluteryl-coenzyme A (HMG-CoA) reductase. The kinetics of in vitro inter-conversion between lactone and its hydroxy acid form has been reported by Kearney et al (1993) and Won (1994), its application for the estimation of lovastatin in the bioequivalence study has not been reported till date
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