Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin

• Published in: Journal of pharmaceutical sciences Vol. 80; no. 9; p. 830
• Main Authors: Serajuddin, A T, Ranadive, S A, Mahoney, E M
• Format: Journal Article
• Language: English
• Published: United States 01-09-1991
• Subjects: Anticholesteremic Agents - pharmacology; Chromatography, High Pressure Liquid; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin - analogs & derivatives; Lovastatin - pharmacology; Pravastatin - pharmacology; Simvastatin; Solubility; Structure-Activity Relationship
• ISSN: 0022-3549
• DOI: 10.1002/jps.2600800905

The apparent octanol-water partition coefficients (Po/w) and aqueous solubilities for four 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors [pravastatin, lovastatin (mevinolin), mevastatin (compactin), and simvastatin (synvinolin)] were compared. Pravastatin is highly hydrophilic compared with lovastatin, mevastatin, or simvastatin. Pravastatin is clinically used as the active hydroxy acid, while the other three compounds are administered as prodrug lactones which, over a period of time, convert in vivo to their respective active hydroxy acid forms. The order of the Po/w values of the hydroxy acid forms was pravastatin much less than mevastatin less than lovastatin less than simvastatin at each pH evaluated, with approximate ratios of 1:25:75:200, respectively. The relative order and the ratios of partition coefficients for the lactone forms were similar to those for the hydroxy acid forms. In addition, lovastatin, mevastatin, and simvastatin are virtually insoluble in water, with solubility values ranging from 0.0013 to 0.0015 mg/mL at 23 degrees C. In comparison, pravastatin is hydrophilic, as demonstrated by the greater than 100-fold greater solubility of its lactone form (0.18 mg/mL). The greater hydrophilicity of pravastatin may explain its reported lower permeation into nonhepatic cells and the selectivity with respect to inhibition of cholesterol synthesis.