This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Tanzer, J.M. Articles by Willard, A.K. Search for Related Content PubMed PubMed Citation Articles by Tanzer, J.M. Articles by Willard, A.K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB PILOCARPINE Social Bookmarking                         What's this?

A Pharmacokinetic and Pharmacodynamic Study of Intravenous Pilocarpine in Humans

Departments of Oral Diagnosis, School of Dental Medicine; University of Connecticut Health Center, Farmington, CT 06030, Department of Laboratory Medicine; University of Connecticut Health Center, Farmington, CT 06030

P.A. Kramer

Department of Pharmaceutical Sciences, School of Pharmacy; University of Connecticut Health Center, Farmington, CT 06030, Department of Laboratory Medicine; University of Connecticut Health Center, Farmington, CT 06030; University of Connecticut Health Center, Farmington, CT 06030

P. Schulman

Department of Medicine, School of Medicine

A.K. Willard

Department of Clinical Research Center5; University of Connecticut Health Center, Farmington, CT 06030; University of Connecticut Health Center, Farmington, CT 06030

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 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.

Key Words: Pilocarpine • humans • intravenous • pharmacokinetics • salivation

REFERENCES

• Barnes PJ (1994). Anticholinergic therapy. In: Drugs and the lung. Page CP, Metzger WJ, editors. New York: Raven Press, pp. 47-67.
• Boxenbaum H. (1980). Interspecies variation in liver weight, hepatic blood flow and antipyrine intrinsic clearance: Extrapolation of data to benzodiazepines and phenytoin. J Pharmacokinet Biopharm 8:165-176.[CrossRef][Medline] [Order article via Infotrieve]
• Boxenbaum HG, Riegelman S., Elashoff RM (1974). Statistical estimations in pharmacokinetics. J Pharmacokinet Biopharm 2:123-148.[CrossRef][Medline] [Order article via Infotrieve]
• Buckley JP (1910). Modern dental materia medica, pharmacology and therapeutics. Philadelphia, PA: Blakiston's Son & Company, pp. 217-224.
• Chiou WL (1979). Potential pitfalls in conventional pharmacokinetic studies: Effects of the initial mixing of drug in blood and the pulmonary first-pass elimination. J Pharmacokinet Biopharm 7:527-536.[CrossRef][Medline] [Order article via Infotrieve]
• Daniels TE, Silverman S. Jr, Michalski JP, Greenspan JS, Sylvester RA, Talal N. (1975). The oral component of Sjogren's syndrome. Oral Surg Oral Med Oral Pathol 39:875-885.[CrossRef][Medline] [Order article via Infotrieve]
• De Girolami U., Smith TW, Henin D., Hauw JJ ( 1990). Neuropathology of the acquired immunodeficiency syndrome. Arch Pathol Lab Med 114:643-655.[Medline] [Order article via Infotrieve]
• DeVane CL, Jarecke CR (1992). Cyclic antidepressants. Chapter 33. In: Applied pharmacokinetics. Evans WE, Schentag JJ, Jusko WJ, editors. 3rd ed. Vancouver, WA: Applied Therapeutics, Inc., pp. 1-47.
• Drug Topics Redbook (1989). Oradell, NJ: Medical Economics Co., p. 562.
• Fox PC, Atkinson JC, Macynski AA, Wolff A., Kung DS, Valdez IH, et al. (1991). Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 151:1149-1152.[Abstract/Free Full Text]
• Fox PC, van der Ven PF, Sonies BC, Weiffenbach JM, Baum BJ ( 1985). Xerostomia: Evaluation of a symptom with increasing significance. J Am Dent Assoc 110:519-525.[Abstract]
• Fox PC, van der Ven PF, Baum BJ, Mandel ID (1986). Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction. Oral Surg Oral Med Oral Pathol 61:243-248. Gibaldi M. (1991). Biopharmaceutics and clinical pharmacokinetics. 4th ed. Philadelphia, PA: Lea & Febiger, pp. 14-23 and 203-233.
• Greenberg MS (1984). Salivary gland disease. In: Burket's oral medicine. Lynch MA, Brightman VJ, Greenberg MS, editors. New York: Lippincott Company, pp. 482-500. Greenspan D., Daniels TE (1987). Effectiveness of pilocarpine in postradiation xerostomia. Cancer 59:1123-1125.[CrossRef][Medline] [Order article via Infotrieve]
• Hughes GRV, Whaley K. (1972). Sjogren's syndrome. Br Med J 4:533-536.[Abstract/Free Full Text]
• Iwabuchi Y., Masuhara T. (1992a). Subtype of the muscarinic receptor that mediates salivary secretion in the rat sublingual gland. Asia Pacific J Pharmacol 7:197-202. Iwabuchi Y., Masuhara T. (1992b). Subtypes of the muscarine receptors that are involved in pilocarpine-induced secretion of saliva from rat sublingual glands. Asia Pacific J Pharmacol 7:271-276.
• Jusko WJ (1992). Guidelines for collection and analysis of pharmacokinetic data. Chapter 2. In: Applied pharmacokinetics. Evans WE, Schentag JJ, Jusko WJ, editors. Vancouver, WA: Applied Therapeutics Inc., pp. 1-43. Kirchheim HR (1976). Systemic arterial baroreceptor reflexes. Physiol Rev 56:100-177.[Free Full Text]
• Kremer JMH, Wilting J., Janssen LHM (1988). Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacolog Rev 40:1-47.[Medline] [Order article via Infotrieve]
• Johnson G., Barenthin I., Westphal P. (1984). Mouth dryness among patients in longterm hospitals. Gerodontology 3:197-203. Johnson JT, Ferretti GA, Nethery WJ, Valdez IH, Fox PC, Ng D., et al. (1993). Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 329:390-395.[Abstract/Free Full Text]
• Mandel ID (1979). In defense of the oral cavity. In: Saliva and dental caries. Kleinberg I, Ellison SA, Mandel ID, editors. New York: Information Retrieval, Inc., pp. 473-491.
• Mandel ID, Katz R., Zengo A., Kutscher AH, Greenberg RA, Katz S., et al. (1967). The effect of pharmacologic agents on salivary secretion and composition in man. 1. Pilocarpine, atropine and anticholinesterases. J Oral Ther Pharmacol 4:192-199.[Medline] [Order article via Infotrieve]
• Piafsky KM, Borga O., Odar-Cederlof I., Johansson C., Sjoqvist F. (1978). Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma a-1 acid glycoprotein. N Engl J Med 299:1435-1439.[Abstract]
• Schiodt M., Greenspan D., Daniels TE, Nelson J., Leggot PJ, Wara DW, et al. (1989). Parotid gland enlargement and xerostomia associated with labial sialadenitis in HIVinfected patients. J Autoimmun 2:415-425.[CrossRef][Medline] [Order article via Infotrieve]
• Sreebny LM, Valdini A. (1987). Xerostomia, a neglected symptom. Arch Intern Med 147:1333-1337.[Abstract/Free Full Text]
• Talal N. (1984). How to recognize and treat Sjögren's syndrome. Drug Ther Hosp 9:80-87.
• Weaver ML, Tanzer JM, Kramer PA (1992a). High performance liquid chromatographic determination of pilocarpine in plasma. J Chromatogr Biomed Appl 581:293-296.
• Weaver ML, Tanzer JM, Kramer PA (1992b). Pilocarpine disposition and salivary flow responses following intravenous administration to dogs. Pharm Res 9:1064-1069. Weaver ML, Tanzer JM, Kramer PA (1992c). Salivary flow induction by buccal permucosal pilocarpine in anesthetized beagle dogs. J Dent Res 71:1762-1767.

Journal of Dental Research, Vol. 74, No. 12, 1845-1849 (1995)
DOI: 10.1177/00220345950740120701


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				T. Endo, M. Ban, K. Hirata, A. Yamamoto, Y. Hara, and Y. Momose Involvement of CYP2A6 in the Formation of a Novel Metabolite, 3-Hydroxypilocarpine, from Pilocarpine in Human Liver Microsomes Drug Metab. Dispos., March 1, 2007; 35(3): 476 - 483. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Tanzer, J.M. Articles by Willard, A.K. Search for Related Content PubMed PubMed Citation Articles by Tanzer, J.M. Articles by Willard, A.K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB PILOCARPINE Social Bookmarking                         What's this?