The enhanced nonenzymatic isomerization of pravastatin at SQ 31,906, a relatively inactive metabolite, has been demonstrated to occur on exposure to gastric acidity in humans. However, the effect of gastric metabolism on the pharmacodynamics of pravastatin has not been studied. In addition, it was hypothesized that some individuals may be more extensive gastric metabolizers than others. Sixteen men received 4 weeks of oral therapy with pravastatin 10 mg after a 6-week drug washout diet run-in period. Pharmacokinetic and pharmacodynamic parameters were determined after 8 hours of serum sampling on the final day of therapy. Patients with a metabolic ratio for area under the concentration-time curve (AUC0-8 of pravastatin/AUC0-8 of SQ 31,906) of less than 1.6 had a significantly lower reduction in total and low-density lipoprotein (LDL) cholesterol compared with those with a ratio> 1.6. An enteric formulation of pravastatin should increase the bioavailability of pravastatin and enhanced lipid-lowering efficacy.