The disposition of a human relaxin (hRlx-2) in pregnant and nonpregnant rats.
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 micrograms/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 (Vc) was 48-79 ml/kg and the volume of distribution at steady state (Vss) was 271-336 ml/kg. Increasing the dose to 463 micrograms/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.
Cossum
P A
PA
Department of Safety Evaluation, Genentech, Inc., South San Francisco, California 94080.
Dwyer
K A
KA
Roth
M
M
Chen
S A
SA
Moffat
B
B
Vandlen
R
R
Ferraiolo
B L
BL
D000818:Animals; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D010477:Perfusion; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012065:Relaxin / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D012065:Relaxin