Pharmacokinetics metabolism
PRAVACHOL (pravastatin sodium) is administered orally in the active form. In clinical
pharmacology studies in man, pravastatin is rapidly absorbed, with peak plasma levels of
parent compound attained 1 to 1.5 hours following ingestion. Based on urinary recovery
of radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute
bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces
systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken
with, or 1 hour prior, to meals.
Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66),
which is its primary site of action, and the primary site of cholesterol synthesis and of
LDL-C clearance. In vitro studies demonstrated that pravastatin is transported into
hepatocytes with substantially less uptake into other cells. In view of pravastatin’s
apparently extensive first-pass hepatic metabolism, plasma levels may not necessarily
correlate perfectly with lipid-lowering efficacy. Systemic bioavailability
of pravastatin administered following a bedtime dose was decreased 60% compared to
that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy
of pravastatin administered once daily in the evening, although not statistically
significant, was marginally more effective than that after a morning dose. This finding of
lower systemic bioavailability suggests greater hepatic extraction of the drug following
the evening dose. Approximately 50% of the circulating drug
is bound to plasma proteins.
Pravastatin, like other HMG-CoA reductase inhibitors, has variable bioavailability. The
coefficient of variation (CV), based on between-subject variability, was 50% to 60% for
AUC. Pravastatin 20 mg was administered under fasting conditions in adults.
Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces.
After intravenous administration of radiolabeled pravastatin to normal volunteers,
approximately 47% of total body clearance was via renal excretion and 53% by non-renal
routes (i.e., biliary excretion and biotransformation). Since there are dual routes of
elimination, the potential exists both for compensatory excretion by the alternate route as
well as for accumulation of drug and/or metabolites in patients with renal or hepatic
insufficiency.
In a study comparing the kinetics of pravastatin in patients with biopsy confirmed
cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic
patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied
47-fold for cirrhotic patients compared to 6-fold for healthy subjects.
Biotransformation pathways elucidated for pravastatin include: (a) isomerization to 6-epi
pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906), (b) enzymatic ring
hydroxylation to SQ 31,945, (c) ω-1 oxidation of the ester side chain, (d) β-oxidation of
the carboxy side chain, (e) ring oxidation followed by aromatization, (f) oxidation of a
hydroxyl group to a keto group, and (g) conjugation. The major degradation product is
the 3α-hydroxy isomeric metabolite, which has one-tenth to one-fortieth the HMG-CoA
reductase inhibitory activity of the parent compound.
In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was
approximately 27% greater and the mean cumulative urinary excretion (CUE)
approximately 19% lower in elderly men (65 to 75 years old) compared with younger
men (19 to 31 years old). In a similar study conducted in women, the mean AUC for
pravastatin was approximately 46% higher and the mean CUE approximately 18% lower
in elderly women (65 to 78 years old) compared with younger women (18 to 38 years
old).
Pravachol
Cholesterol
Liver enzymes
Drug interactions
Dosage and administration
Pharmacokinetics metabolism
Skeletal muscle
Clinical pharmacology