The Application of lc-r1.1s-ms to study the effects of fasting, food and antacid on the pharmacokinetics of simvastatin in heal thy mala yslan subjects

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dc.contributor.authorAhmed Ali Al-Akhali, Khaled Mohmmed
dc.date.accessioned2015-09-28T07:24:02Z
dc.date.available2015-09-28T07:24:02Z
dc.date.issued2007
dc.description.abstractSimvastatin a lactone analog of lovastatin which is used in the treatment of hypercholesterolemia. Simvastatin lowers plasma cholesterol by inhibiting 3- hydroxy-3-methylglutaryi-CoA reductase. The aims of this study were to develop and validate sufficiently sensitive analytical methods for the determination of simvastatin in plasma. This was followed by a comparative pharmacokinetic study of a single oral dose of 40 mg simvastatin under fasting, food and antacid conditions. The assays are HPLC methods with various detection methods: (1) High performance liquid chromatography-ultraviolet (HPLC-UV); validation of the HPLC-UV revealed precision and accuracy < 9%. Linearity was ranged from 20- 1 000 ng/ml with limit of detection of 15 ng/ml and the limit of quantification of 20 ng/ml was achieved. (2) Liquid chromatography mass spectrometry (LCMS); validation of the LC-MS revealed precision and accuracy< 10%. Linearity was ranged from 0.5-20 ng/ml with limit of detection of 0.4 ng/ml and the limit of quantification of 0.5 ng/ml was achieved. (3) Liquid chromatography tandem mass spectrometry (LC-MS-MS); validation of the LC-MS-MS revealed precision and accuracy< 14%. Linearity was linear range from 0.25-50 ng/ml with limit of detection of 0.125 ng/ml and the limit of quantification of 0.25 ng/ml was achieved. The HPLC-UV was not sensitive in-measuring simvastatin in plasma after oral dosing. The LC-MS-MS method showed better specificity and sensitivity than the LC-MS technique. Thus LC-MS-MS was used for the analysis of plasma samples. A randomized study of 9 Malaysian healthy male volunteers aged 22-49 years old, on 3 groups crossover design in three blocks of 3 subjects was used for a comparative pharmacokinetic study of simvastatin. In first group, the fasting volunteers were given a single dose of 40 mg tablet of simvastatin. In the second group, the volunteers were given 40 mg tablet of simvastatin with liquid antacid (1 00 mL). In the third group, the volunteers were given local food before the administration of 40 mg simvastatin. The wash-out period between groups was one week. Food and antacid produced higher AUCa-24, Cmax and T max values of simvastatin as compared with fasting condition. The Ke. and Vd did not show any significant difference between fasting, food and antacid conditions. The t112 was slightly shorter in food than antacid and fasting conditions. Cl was slightly lower in antacid than fasting conditions. Food and antacid have same effect and did not show any significant difference on AUCa-24. Cmax. Ke. T max. Cl and Vd on simvastatin. The results showed that the food and antacid increased the bioavailability of simvastatin by increasing the pH of gastrointestinal tract Consequently, that may be lead to increase the stability of lactone form of simvastatin as well as improve the dissolution of the simvastatin by increasing the gastric residence time. It was concluded that simvastatin bioavailability is pH dependent.en_US
dc.identifier.urihttp://hdl.handle.net/123456789/1238
dc.language.isoenen_US
dc.subjectFood and antaciden_US
dc.subjectHealthy Malayslanen_US
dc.subjectPharmacokineticsen_US
dc.titleThe Application of lc-r1.1s-ms to study the effects of fasting, food and antacid on the pharmacokinetics of simvastatin in heal thy mala yslan subjectsen_US
dc.typeThesisen_US
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