Effect of Calcimimetic Agent, KRN568, on Gastrin Secretion in Healthy Subjects

• Published in: ENDOCRINE JOURNAL Vol. 47; no. 5; pp. 517 - 523
• Main Authors: IGARASHI, TETSUYA, OGATA, ETSURO, MARUYAMA, KAZUNOBU, FUKUDA, TSUYOSHI, AZUMA, JUNICHI
• Format: Journal Article
• Language: English
• Published: Japan The Japan Endocrine Society 2000
• Subjects: Administration, Oral; Adult; Aniline Compounds - pharmacokinetics; Aniline Compounds - pharmacology; Calcimimetics; Calcium - agonists; Calcium-sensing receptor; Cytochrome P-450 Enzyme System - genetics; Gastrin; Gastrins - blood; Gastrins - metabolism; Genotype; Humans; Male; Phenethylamines; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Propylamines
• DOI: 10.1507/endocrj.47.517
• EISSN: 1348-4540
• ISSN: 0918-8959

KRN568 is a calcimimetic compound which acts on the calcium sensing receptors (CaR) on the parathyroid gland to suppress secretion of PTH. A recent report has demonstrated that CaRs are expressed on cultured human antral gastrin cells and that gastrin secretion is stimulated by an increase in extracellular calcium level. However, the effect of KRN568 on serum gastrin levels has yet to be clinically assessed. We therefore studied the effect of this calcimimetic on gastrin secretion in healthy subjects enrolled in the phase 1 study for KRN568 currently male volunteers at fasting and after meal. One subject proved to be a poor metabolizer (PM) for this compound and showed more than 10-fold high concentrations of plasma KRN568 (fasting Cmax 90.8 and non-fasting 83.8ng/ml) compared to the other 5 individuals (Cmax 6.5±2.2 and 7.4±1.6ng/ml, respectively). Plasma gastrin levels showed mild but apparent increase (from 30 to 125pg/ml) in this particular subject, while there were no significant increases in the other five people (from 34±6 to 63±3pg/ml) after oral administration of 400mg KRN568 at fasting. In the PM, administration of KRN568 resulted in extraordinarily high serum drug levels associated with transient increase of gastrin levels. This observation suggested that calcium-induced stimulation of gastrin secretion in human was mediated by a mechanism involving CaR. Potential side effects related to the increased gastrin secretion may be warranted in the practical use of this compound.