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Pilocarpine is used orally to treat xerostomia but patients vary widely in their response and ability to tolerate this drug. To elucidate the potential pharmacokinetic contribution of serum to this variability, the enzymatic hydrolysis of pilocarpine in human serum in vitro was investigated using a stability indicating HPLC assay. The reaction at 37 degrees C follows Michaelis-Menten kinetics (K(m) = 2.78 +/- 0.48 mmol/liter, Vmax = 79 +/- 13 nmol min-1 ml 1; n = 5) and produces pilocarpic acid as the only detectable product. The distribution of pilocarpine esterase activity in a group of healthy young adults at age 21 (n = 163; 87 males, 76 females) was examined by incubating serum samples with pilocarpine (10 mmol/ liter) at 37 degrees C for 60 min. The distribution was positively skewed and ranged from 4 to 132 nmol min-1 ml-1 with a mean value of 55 +/- 23 nmol min-1 ml 1. The means for males and females were not significantly different. Similar measurements in xerostomia patients undergoing treatment with oral pilocarpine showed that those with higher serum esterase activity tolerated pilocarpine well and tended to require higher doses for relief of xerostomia, whereas those with low activity were sensitive to the adverse effects of the drug and were adequately treated with a lower dose. The results suggest that at least some of the variability in response to oral pilocarpine is due to differences in serum pharmacokinetics.