Abstract
A range of bolus doses of 14 C-chlorothiazide and unlabeled drug (6.7–30 mg/kg) were administered to each of three unanesthetized rhesus monkeys with and without concurrent probenecid dosing. Plasma up to 4 h and urine up to 24 h were sampled frequently. Apparent terminal plasma half-lives ranged from 18 to 25 min in the absence of probenecid. No apparent trend was noted for the volume of distribution of the central compartment calculated from estimated plasma concentrations at time zero. For chlorothiazide studies, an average of 92% of the dose was recovered in urine by 24 hr. Plasma and urinary clearances at low doses were 20 to 50% higher than those found with higher doses. These dose-dependent clearances for chlorothiazide were found at doses parallel to the most often prescribed clinical doses in humans on a g chlorothiazide per kg body weight basis. Clearances in the presence of probenecid decreased two-to four-fold over those seen without probenecid. Incremental renal clearances of chlorothiazide in the studies with and without probenecid were also evaluated. Curvilinear segments characteristic of dose-dependent kinetics were demonstrated in graphs of urinary excretion rate versus plasma concentrations. Values of Michaelis-Menten constants Vmax and Km were calculated for renal excretion of chlorothiazide by active transport after intravenous doses in all three monkeys. The contribution of glomerular filtration to chlorothiazide renal clearance was found to be negligible. Values of the constant KI (the concentration of the probenecid competitive inhibitor of chlorothiazide, which doubles the apparent Km value of chlorothiazide) were calculated using the previously calculated Vmax and Km values.
Similar content being viewed by others
References
F. C. Novelle, and J. M. Sprague. Benzothiadiazine dioxides as novel diruretics.J. Am. Chem. Soc. 79:2028–2029 (1957).
L. S. Goodman and A. Gilman.The Pharmacological Basis of Therapeutics, 5th ed., Macmillan, New York, 1975, pp. 828–832.
L. Joubert, and C. Radouco-Thomas. A study in human pharmacology: evaluation of four diuretics and a placebo.Canad. Med. Assoc. J. 99:57–63 (1968).
R. I. Ogilvie and J. Ruedy. Treatment of hypertension with hydrochlorothiazide and spironolactone.Canad. Med. Assoc. J. 101:61–64 (1969).
P. Kincaid-Smith. The use of duretics in pregnancy.Excerpta Medica 286:281–293 (1973).
S. Sherlock, “Diuretics in Hepatic Disease,”Excerpta Medica 268:270–280 (1973).
D. Beevers, J. Harpur, and M. Hamilton. The long-term treatment of hypertension with thiazide diuretics.Postgrad. Med. J. 47:639–643 (1971).
J. H. Laragh. The mode of action and use of chlorothiazide and related compounds.Circulation 26:121–132 (1962).
F. C. Reubi. The action and use of diuretics in renal disease.Prog. Cardiovasc. Dis. 3: 563–579 (1961).
L. E. Earley and J. Orloff. Thiazide diuretics,Ann. Rev. Med. 15:149–166 (1964).
K. H. Beyer, Jr. and J. E. Baer. The site and mode of action of some sulfonamide-derived diuretics.Med. Clin. N. Am. 59:735–750 (1975).
J. M. Weller and R. L. Malvin. Effects and side-effects of thiazide drugs.Med. Clin. N. Am. 53:1321–1330 (1969).
A. Ando, Y. Orita, Y. Takamitsu, S. Urakabe, D. Shirai, and H. Abe. A quantum chemical study extended to the sulfamyl group of thiazide diuretics.Jap. Cire. J. 34:609–612 (1970).
Y. Orita, A. Ando, Y. Takamitsu, D. Shirai, S. Urakabe, and H. Abe. Studies on Huckel's molecular-orbital calculation (3dπ -2pπ) of the sulfamyl part of thiazide diuretics.Japn. Circ. J. 36:187–190(1972).
Y. Orita, A. Ando, Y. Takamitsu, D. Shirai, S. Urakabe, T. Furukawa, and H. Abe. A quantum-biological analysis of thiazide diuretics and ethacrynic acid,Japn. Circ. J. 32:547–554 (1968).
Y. Orita, A. Ando, Y. Takamitsu, S. Urakabe, T. Furukawa, and H. Abe. A quantumbiological study of the pharmacological action of thiazide diuretics,Japn. Circ. J. 31:441–446 (1967).
H. R. Brettell, J. K. Aikawa, and G. S. Gordon. Studies with chlorothiazide tagged with radioactive carbon (C14) in human beings.Arch. Intern. Med. 106:57–63 (1960).
R. K. Nayak and L. Z. Benet. Use of the unanesthetized rhesus monkey as a model for studying the gastrointestinal absorption of drugs.J. Pharmacokin. Biopharm. 2:417–431 (1974).
J. E. Baer, H. L. Leidy, A. V. Brooks, and K. H. Beyer. The physiological disposition of chlorothiazide (Diuril) in the dog.J. Pharmacol. Exp. Ther. 125:295–302 (1959).
A. G. Zacchei and L. Weidner. GLC determination of probenecid in biological fluids.J. Pharm. Sci. 62:1972–1975 (1973).
C-W. N. Chiang. The interpretation of pharmacokinetic parameters for a drug showing dose-dependent kinetics: studies with probenecid. Thesis, University of California, San Francisco, 1976, pp. 26, 40.
W. J. Dixon, ed.BMD Biomedical Computer Programs, University of California Press, Berkeley, 1974, pp. 677–692.
D. E. Pickering, and H. H. Sussman. Cited in G. H. Bourne, ed.,The Rhesus Monkey, Vol. 1. Anatomy and Physiology, Academic Press, New York, 1975, p. 138–139.
Weigel, Hansen and Smith (1966). Cited in G. H. Bourne, ed.,The Rhesus Monkey, Vol. 1. Anatomy and Physiology, Academic Press, New York, 1975, p. 61.
I. H. Stockley. Mechanisms of drug interaction in the pharmacokinetic phase of drug activity.Am. J. Hosp. Pharm. 27:977–985 (1970).
K. S. Pang, M. Rowland, and T. N. Tozer, In Vivo Evaluation of Michaelis-Menten Constants of Hepatic Drug-Eliminating Systems,Drug Metab. Dispos. 6:197–200 (1978).
J. R. Gillette. Techniques for studying drug metabolism in vitro. In B. LaDu, H. Mandel, and E. Way, (eds.),Fundamentals of Drug Metabolism and Drug Disposition, Williams & Wilkins, Baltimore, 1971, pp. 405–407.
Author information
Authors and Affiliations
Additional information
Supported in part by NIH grants GM 26691 and AM 20884. During the course of this work, Dr. Gustafson received support as an NIH Predoctoral Fellow (GM 00752) and as a Fellow of the American Foundation for Pharmaceutical Education.
Rights and permissions
About this article
Cite this article
Gustafson, J.H., Benet, L.Z. Saturable kinetics of intravenous chlorothiazide in the rhesus monkey. Journal of Pharmacokinetics and Biopharmaceutics 9, 461–476 (1981). https://doi.org/10.1007/BF01060889
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01060889