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-relate d peptide [PTHrP-(1-34)] appear to be equipotent in several rodent mod els. However, continuous iv infusions of these peptides to young human volunteers suggested that a 10-fold higher molar dose of PTHrP was re quired to produce comparable circulating levels of the peptide and bio chemical responses similar to PTH. As PTHrP has a wide variety of targ et 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 appar ently 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 iv injections in a dose of 10.7 nmol. Mea surements of plasma immunoreactive peptide indicated a comparable volu me of distribution for each, but the apparent t(1/2) (8.3 +/- 1.6 min) and plasma clearance (4.0 +/- 1.4 L/min) for hPTHrP were significantl y (P < 0.05) accelerated compared to those of hPTH (t(1/2), 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, calci um, 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 c omparable 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, a nd thus the local target tissue response, could not be estimated in th e present study.