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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Date
2007
Authors
Ahmed Ali Al-Akhali, Khaled Mohmmed
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Abstract
Simvastatin 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.
Description
Keywords
Food and antacid , Healthy Malayslan , Pharmacokinetics