Comparison of the pharmacokinetics of parenteral parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in healthy young humans.
The amino-terminal fragments of human PTH [hPTH-(1-34)] and PTH-related peptide [PTHrP-(1-34)] appear to be equipotent in several rodent models. However, continuous i.v. infusions of these peptides to young human volunteers suggested that a 10-fold higher molar dose of PTHrP was required to produce comparable circulating levels of the peptide and biochemical responses similar to PTH. As PTHrP has a wide variety of target tissues in mammalian species and may, therefore, play a paracrine, rather than an endocrine, hormonal role in vivo, we evaluated whether enhanced metabolic clearance of injected PTHrP might explain its apparently reduced potency as a PTH-like hormone. Ten healthy subjects [age, 25 +/- 9 (+/- SD) yr] received in random order either hPTH-(1-34) or hPTHrP-(1-34) given by bolus i.v. injections in a dose of 10.7 nmol. Measurements of plasma immunoreactive peptide indicated a comparable volume of distribution for each, but the apparent t1/2 (8.3 +/- 1.6 min) and plasma clearance (4.0 +/- 1.4 L/min) for hPTHrP were significantly (P < 0.05) accelerated compared to those of hPTH (t1/2, 10.2 +/- 0.5 min; clearance, 2.0 +/- 0.4 L/min). Peak plasma cAMP levels were 9-fold lower in response to hPTHrP (29.5 +/- 19 vs. 190 +/- 63 pmol/L; P < 0.01), and increases in urinary cAMP excretion were 5-fold lower (2.1 +/- 1.1 vs. 11.2 +/- 3.7 nmol/mmol creatinine; P < 0.01). No major differences were observed in the urinary excretion of phosphate, calcium, or sodium between the two peptides. Although hPTHrP-(1-34) has a 2-fold higher MCR than hPTH-(1-34), this may not explain the more than 5-fold lower plasma or urinary cAMP response to PTHrP in humans. The comparable effects of PTH and PTHrP on urinary phosphate, calcium, and sodium may indicate a non-cAMP-dependent pathway for these responses, although the intracellular pool of cAMP generated to either peptide, and thus the local target tissue response, could not be estimated in the present study.
Fraher
L J
LJ
Department of Medicine, Lawson Research Institute, St. Joseph's Health Center, London, Ontario, Canada.
Klein
K
K
Marier
R
R
Freeman
D
D
Hendy
G N
GN
Goltzman
D
D
Hodsman
A B
AB
D000328:Adult; D002118:Calcium / Q000652:urine; D000242:Cyclic AMP / Q000097:blood / Q000652:urine; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D010710:Phosphates / Q000652:urine; D011506:Proteins / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D012016:Reference Values; D019379:Teriparatide
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010710:Phosphates; D011506:Proteins; D019379:Teriparatide; C054296:parathyroid hormone-related protein (1-34); D000242:Cyclic AMP; D002118:Calcium