Distribution and pharmacokinetics of a potent peptide antagonist of parathyroid hormone and parathyroid hormone-related protein in the rat

J. A. Schetz, C. A. Mayr, J. E. Taylor, M. Rosenblatt, M. Chorev, Thomas P Davis

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Humoral hypercalcemia of malignancy results from the production by cancer cells of parathyroid hormone related protein that activates receptors in bone. Peptide antagonists that block parathyroid hormone receptors in vivo would be instrumental in the clinical treatment of humoral hypercalcemia of malignancy. We report the in vive whole body distribution and blood plasma pharmacokinetics of the parathyroid hormone receptor antagonist [Nle8,18,D-Trp12,monoiodinated Tyr34]bPTH(7-34)amide to determine parameters that are likely to affect its administration regimen. A single intravenously injected dose of [Nle8,18,D-Trp12,monoiodinated Tyr34]bPTH(7-34)amide was rapidly cleared from blood plasma. The plasma concentration reaches a maximum at 10 min (C(max) = 1.93 ± 0.27% of total injected CPM/ml), and the intact PTH derivative was detectable in plasma by HPLC analysis at this time. In vivo binding to plasma proteins was noncovalent. The peptide was rapidly cleared from blood by the liver, and more slowly by the kidney. Radiolabel was detected in excreted feces at 8 hr, but the preferred route of excretion was renal as judged by significant counts in excreted urine. Absorption of labeled peptide by skin and bone was sustained. Strong and sustained absorption also occurred in the vas deferens, seminal vesicle and hypothalamus. Given the rapid clearance of antagonist, multiple or sustained dosing schemes might be necessary to achieve the desired pharmacological effect. The high counts in liver at early time points after i.v. injection suggest that other routes of administration that do not bypass the hepatic first-pass effect would result in very low blood levels of drug.

Original languageEnglish (US)
Pages (from-to)1456-1462
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume274
Issue number3
StatePublished - 1995
Externally publishedYes

Fingerprint

Parathyroid Hormone-Related Protein
Parathyroid Hormone
Pharmacokinetics
Peptides
Amides
Liver
Parathyroid Hormone Receptors
Parathyroid Hormone Receptor Type 1
Bone and Bones
Parathyroid Neoplasms
Vas Deferens
Seminal Vesicles
Feces
Hypothalamus
Blood Proteins
High Pressure Liquid Chromatography
Urine
Pharmacology
Kidney
Skin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Distribution and pharmacokinetics of a potent peptide antagonist of parathyroid hormone and parathyroid hormone-related protein in the rat. / Schetz, J. A.; Mayr, C. A.; Taylor, J. E.; Rosenblatt, M.; Chorev, M.; Davis, Thomas P.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 274, No. 3, 1995, p. 1456-1462.

Research output: Contribution to journalArticle

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