title: Pharmacokinetics and hepatic extraction of recombinant human parathyroid hormone, hPTH (1-34), in rat, dog, and monkey.
abstract: 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.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46285, USA. jones_karen_o@lilly.com
authors.forename: Karen O
authors.initials: KO
authors.lastname: Jones
authors.forename: Godfried
authors.initials: G
authors.lastname: Owusu-Ababio
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Vick
authors.forename: M Amin
authors.initials: MA
authors.lastname: Khan
mesh_terms: 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
chemical_list: D007202:Indicators and Reagents; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011994:Recombinant Proteins