Zocor pharmacokinetics and molecular data: Difference between revisions
No edit summary |
Matt Pijoan (talk | contribs) m (Reverted edits by AngelSlayerw3NjO (talk) to last revision by NNethala) |
||
| Line 1: | Line 1: | ||
=== | {{CMG}} | ||
==Pharmacokinetics== | |||
<font size="4">[[Zocor pharmacokinetics and molecular data#Mechanism|Mechanism]]</font> | |||
<br> | |||
<br> | |||
<font size="4">[[Zocor pharmacokinetics and molecular data#Absorption|Absorption]]</font> | |||
<br> | |||
<br> | |||
<font size="4">[[Zocor pharmacokinetics and molecular data#Metabolites|Metabolites]]</font> | |||
<br> | |||
---- | |||
<br> | |||
===Mechanism=== | |||
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent | Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent | ||
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in | inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in | ||
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, | pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, | ||
active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. | active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.''[[Zocor pharmacokinetics and molecular data#Pharmacokinetics|Return to top]]'' | ||
<br> | <br> | ||
=== | ===Absorption=== | ||
Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of simvastatin (estimated to be > 60% in man), the availability of drug to the general circulation is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reaches the general circulation as active inhibitors. Following administration of simvastatin tablets, the coefficient of variation, based on between-subject variability, was approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the general circulation. | Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of simvastatin (estimated to be > 60% in man), the availability of drug to the general circulation is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reaches the general circulation as active inhibitors. Following administration of simvastatin tablets, the coefficient of variation, based on between-subject variability, was approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the general circulation.''[[Zocor pharmacokinetics and molecular data#Pharmacokinetics|Return to top]]'' | ||
<br> | <br> | ||
=== | ===Metabolites=== | ||
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human | Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human | ||
plasma proteins. Animal studies have not been performed to determine whether simvastatin crosses the | plasma proteins. Animal studies have not been performed to determine whether simvastatin crosses the | ||
| Line 16: | Line 28: | ||
The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of | The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of | ||
simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma | simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma | ||
concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 80 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. | concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 80 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.''[[Zocor pharmacokinetics and molecular data#Pharmacokinetics|Return to top]]'' | ||
<br> | |||
<br> | |||
---- | |||
<br> | |||
{{FDA}} | |||
Latest revision as of 14:40, 20 December 2011
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pharmacokinetics
Mechanism
Absorption
Metabolites
Mechanism
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent
inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in
pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis,
active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.Return to top
Absorption
Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of simvastatin (estimated to be > 60% in man), the availability of drug to the general circulation is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reaches the general circulation as active inhibitors. Following administration of simvastatin tablets, the coefficient of variation, based on between-subject variability, was approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the general circulation.Return to top
Metabolites
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human
plasma proteins. Animal studies have not been performed to determine whether simvastatin crosses the
blood-brain and placental barriers. However, when radiolabeled simvastatin was administered to rats,
simvastatin-derived radioactivity crossed the blood-brain barrier.
The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of
simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma
concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 80 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.Return to top
Adapted from the FDA Package Insert.