Abstract
The pharmacokinetics and tissue distribution of a human relaxin were investigated after intravenous (iv) bolus administration to pregnant or nonpregnant rats. Human gene-2 relaxin (hRlx-2) serum concentrations after iv bolus administration were described as the sum of three exponentials. The pharmacokinetics were comparable in pregnant and nonpregnant rats. The serum clearance (CL) was 7.4–10.2 ml/min/kg at doses of 46–93 µg/kg and was linear in this range. The half-lives were 1.1–2.0, 15.1–16.4, and 53.7–67.9 min, respectively. The volume of the central compartment (V c) was 48–79 ml/kg and the volume of distribution at steady state (V ss) was 271–336 ml/kg. Increasing the dose to 463 µg/kg increased the dose-corrected area under the serum concentration–time curve and significantly decreased CL and Vss. The distribution of radioactivity in the tissues of pregnant rats was followed after iv bolus dosing with hRlx-2 internally labeled with 35S-cysteine. Comparison of the extent of organ uptake of radiolabel after 35S-hRlx-2 or 35S-cysteine administration suggested that the kidneys were the principal site of uptake; the liver was of secondary importance. In perfusion experiments utilizing livers isolated from pregnant or nonpregnant rats, 36–52% of the dose of hRlx-2 was cleared from the perfusate in 2 hr. These studies showed that the pharmacokinetics of hRlx-2 in rats appeared to be unaffected by pregnancy and suggested that the kidneys and liver both play a role in the elimination of hRlx-2.
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REFERENCES
G. Weiss, E. M. O'Byrne, and B. G. Steinetz. Relaxin: A product of the human corpus luteum of pregnancy. Science 194:948–949 (1976).
P. Vasilenko and J. P. Mead. Growth-promoting effects of relaxin and related compositional changes in the uterus, cervix and vagina of the rat. Endocrinology 120:1370–1376 (1987).
O. D. Sherwood, V. E. Crnekovic, W. L. Gordon, and J. E. Rutherford. Radioimmunoassay of relaxin throughout pregnancy and during parturition in the rat. Endocrinology 107:691–694 (1980).
A. H. MacLennan, R. D. Green, and G. D. Greenwood. Ripening of the human cervix and induction of labour with purified porcine relaxin. Lancet 1:220–223 (1980).
C. H. Birnberg and M. W. Abitbol. Refined relaxin and length of labor. Obsiet. Gynecol. 10:366–370 (1957).
E. M. O'Byrne, S. Brindle, J. Quintavalla, C. Strawinski, M. Tabachnick, and B. G. Steinetz. Tissue distribution of injected 125I-labeled porcine relaxin; Organ uptake, whole-body autoradiography and renal concentration of radiometabolites. Ann.N.Y. Acad. Sci. 380:187–197 (1982).
S. H. Cheah and O. D. Sherwood. Target tissues for relaxin in the rat. Endocrinology 106:1203–1209 (1980).
B. L. Ferraiolo, M. Cronin, C. Bakhit, M. Chestnut, R. Lyon, and M. Roth. Pharmacokinetics and pharmacodynamics of relaxin in mice. Endocrinology 125:2922–2926 (1989).
B. L. Ferraiolo, J. Winslow, G. Laramee, A. Celniker, and P. Johnston. Pharmacokinetics and metabolism of human relaxins in rhesus monkeys. Pharm. Res. 8:1032–1038 (1991).
P. D. Johnston, J. Burnier, S. Chen, D. Davis, H. Morehead, M. Remington, M. Struble, G. Tregear, and H. Niall. Structure-function studies on human relaxin. Peptides: Structure and function. Proceedings of the Ninth American Peptide Symposium, Pierce Chemical Company, 1985, pp. 683–686.
R. E. Billings, R. E. McMahon, J. Ashmore, and S. R. Wagle. The metabolism of drugs in isolated rat hepatocytes. A comparison with in vivo drug metabolism and drug metabolism in subcellular liver fractions. Drug Metab. Dispos. 5:518–526 (1977).
C. Lucas, L. N. Bald, M. C. Martin, R. B. Jaffe, D. W. Drolet, M. Mora-Worms, G. Bennett, A. B. Chen, and P. D. Johnston. An enzyme-linked immunosorbent assay to study human relaxin in human pregnancy and in pregnant rhesus monkeys. J. Endocrinol. 120:449–457 (1989).
W. O. Caster, J. Poncelet, A. B. Simon, and W. D. Armstrong. Tissue weights of the rat. I. Normal values determined by dissection and chemical methods. Proc. Soc. Exp. Biol. Med. 91:122–126 (1956).
C. A. Owen. Distribution of copper in the rat. Am. J. Physiol. 207:446–448 (1964).
P. A. Cossum, D. E. Hill, J. R. Bailey, J. H. Anderson, and W. Slikker. Transplacental passage of a human relaxin administered to rhesus monkeys. J. Endocrinol. 130:339–345 (1991).
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Cossum, P.A., Dwyer, K.A., Roth, M. et al. The Disposition of a Human Relaxin (hRlx-2) in Pregnant and Nonpregnant Rats. Pharm Res 9, 419–424 (1992). https://doi.org/10.1023/A:1015863507496
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DOI: https://doi.org/10.1023/A:1015863507496