Altering metabolic profiles of drugs by precision deuteration: reducing mechanism-based inhibition of CYP2D6 by paroxetine.

Selective deuterium substitution as a means of ameliorating clinically relevant pharmacokinetic drug interactions is demonstrated in this study. Carbon-deuterium bonds are more stable than corresponding carbon-hydrogen bonds. Using a precision deuteration platform, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium.

Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a 2-year study in Fischer 344 rats.

The carcinogenic potential of human parathyroid hormone 1-84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 microg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density.

Quantification of recombinant human parathyroid hormone (rhPTH(1-84)) in human plasma by immunoassay: commercial kit evaluation and validation to support pharmacokinetic studies.

Immunoassays utilizing commercial kits designed for diagnostic use can be adapted and validated to meet Good Laboratory Practice (GLP) requirements to support pharmacokinetic (PK) studies. We illustrate in this paper a systematic approach for commercial kit evaluation and GLP-compliant method validation to establish selectivity, sensitivity, linearity, accuracy, precision and stability. Immunoassay kits for human parathyroid hormone (hPTH) quantification from three different vendors were assessed in a side-by-side comparison for their suitability for the PK analysis of recombinant humanPTH (rhPTH) in EDTA plasma.

Identification of carboxyl-terminal peptide fragments of parathyroid hormone in human plasma at low-picomolar levels by mass spectrometry.

For decades, researchers have tried to identify the primary structures of circulating carboxyl-terminal parathyroid hormone (C-PTH) peptide fragments that may be present at only picomolar levels in human plasma. Although immunoassays and radiosequencing techniques have provided valuable fragment characterizations, no analysis has successfully determined their exact primary structures. In this work, for the first time, four human C-PTH peptide fragments, hPTH(34-84), hPTH(37-84), hPTH(38-84), and hPTH(45-84), have been identified from human plasma using MS-based methods.