A pharmacokinetic and pharmacodynamic study of intravenous pilocarpine in humans.
Pilocarpine (P) is of potential utility in the treatment of xerostomia. Because optimal development of P dosage forms for humans requires that its pharmacokinetics and pharmacodynamics be defined, this intravenous study of its disposition and associated salivary responses was performed. In a hospital setting, two healthy female subjects were given a series of graded doses of intravenous P or placebo to stimulate salivary secretion. Plasma levels of P, heart rate, blood pressure, and respiratory rate were simultaneously monitored. Other objective and subjective physiological parameters were assessed. Plasma concentrations of P declined either mono- or bi-exponentially with time, and brisk initial salivation was followed by prolonged salivation at doses > or = 1 mg. At doses between 0.5 and 3.5 mg, dose-independent pharmacokinetic parameters included a small steady-state volume of distribution (2.4 to 3.0 L/kg), a high plasma clearance (0.026 to 0.03 L/kg/min), and a mean residence time of approximately 100 min. The cumulative volume of whole saliva secreted during the first 3 h post-dose was linearly related to the area under the plasma concentration-time curve. Plasma concentrations from 1 to 42 ng/mL were associated with significant levels of salivation. The pharmacokinetic linearity of the system and proportionality between the area under plasma concentration-time curves and overall salivary response have important implications for the design and utilization of pilocarpine dosage forms.
Tanzer
J M
JM
Department of Oral Diagnosis, School of Dental Medicine, University of Connecticut Health Center, Farmington 06030, USA.
Kramer
P A
PA
Schulman
P
P
Willard
A K
AK
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010862:Pilocarpine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012044:Regression Analysis; D012119:Respiration / Q000187:drug effects; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D012472:Salivation / Q000187:drug effects*; D012636:Secretory Rate / Q000187:drug effects; D016037:Single-Blind Method
D018721:Muscarinic Agonists; D010862:Pilocarpine