Pravachol Clinical Pharmacology

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Pravachol - Clinical Pharmacology [Pravastatin]

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 cirrho-sis (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 3 -hydroxyisomer of pravastatin (SQ 31,906),

(b) enzymatic ring hydroxy-lation to SQ 31,945,

(c) -1 oxidation of the ester side chain,

(d) -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 3 -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). In both studies, C max , T max and t values were similar in older and younger subjects.