Pharmacokinetics and hepatic extraction of recombinant human parathyroid hormone, hPTH (1-34), in rat, dog, and monkey.
The pharmacokinetics (PK) and hepatic extraction (E(H)) of human PTH (1-34), hPTH (1-34), were characterized in rat, dog, and monkey, following intraportal (IPO) and intravenous (IV) bolus administration. hPTH (1-34) was administered to Sprague-Dawley rats (2, 10, 100 microg/kg), beagle dogs (3, 6 microg/kg), and rhesus monkeys (6, 30 microg/kg). Serum concentrations of immunoreactive hPTH (1-34) were used to derive PK parameters. IPO bioavailability (F(IPO)) was determined by comparing dose-normalized serum exposure (i.e., AUC(IPO)/AUC(IV)). E(H) was estimated as 1-F(IPO). In all species, greater than dose-proportional increases in exposure (i.e., C(max) and AUC) were observed for both routes. Dose-dependent disposition (i.e., time-average clearance (CL) and half-life (t(1/2)) were observed in all three species. In rats, E(H) values of 71% (2 microg/kg), 35% (10 microg/kg), and <1% (100 microg/kg) were obtained. In dogs, E(H) values of 90% (3 microg/kg) and 66% (6 microg/kg) were obtained. In monkeys, E(H) values of 25% (6 microg/kg) and <1% (30 microg/kg) were observed. In conclusion, hPTH (1-34) is subject to hepatic first pass extraction in rat, dog, and monkey with evidence of saturation in the rat. Saturable hepatic extraction in dog and monkey is inconclusive due to the limited dose range investigated.
Jones
Karen O
KO
Eli Lilly and Company, Indianapolis, Indiana 46285, USA. jones_karen_o@lilly.com
Owusu-Ababio
Godfried
G
Vick
Andrew M
AM
Khan
M Amin
MA
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D003627:Data Interpretation, Statistical; D004285:Dogs; D007202:Indicators and Reagents; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics
D007202:Indicators and Reagents; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011994:Recombinant Proteins