METABOLISM, PHARMACOKINETICS, TISSUE DISTRIBUTION, AND EXCRETION OF [¹⁴C]CP-424391 IN RATS

Abstract

ABSTRACT:CP-424391, 2-amino-N-[3aR-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1R-benzyloxymethyl-2-oxoethyl]-isobutyramide, is an orally active growth hormone secretagogue currently being developed. In this study, we investigated the metabolic fate and disposition of radiolabeled CP-424391 in rats. Following 15 mg/kg single oral administration to Sprague-Dawley rats, 91% of the radiolabeled dose was recovered. Feces was the major route of excretion: 77% of the dose recovered in feces of the female rat and 84% in the male. Excretion in the urine was 15% in the female rat compared with 7% in the male. Both fecal and urinary metabolic profiles were consistent in both genders. The metabolic pathways of CP-424391 were oxidation at the benzyl group of the O-benzylserine moiety, N-demethylation of pyrazolidine, and/or Odebenzylation. In circulation, CP-424391 was absorbed within the first hour to an average apparent C max of 1.44 g/ml. CP-424391 accounts for about 40% of radioactivity area under the plasma concentrationtime curve and C max in circulation. The plasma terminal elimination half-life of CP-424391 was 2.4 h and for total radioactivity was 2.8 h. The radioactivity was widely distributed in all tissues except for the central nervous system. [ The growth hormone (GH) is a pulsatile hormone controlled in part by hypothalamus (Rizvi and Arslan, 1998). It exerts direct effect on protein and on carbohydrate and lipid metabolism, and controls the rate of skeletal and visceral growth (Salomon et al., 1996;Tsoshima T, 1998; Russell-Jones and Umpleby 1999). For reasons not yet fully understood, GH secretion gradually declines during normal aging (Corpas et al., 1993;Veldhuis et al., 1997). This decline with age reflects changes in both frequency and magnitude of secretory pulses. A spectrum of physiologic changes occur that are reminiscent of the adult GH deficiency syndrome (Jorgensen et al., 1994). The deleterious consequences of this deficiency include increased visceral adiposity, reduced lean body mass and muscle-to-fat ratio, osteopenia, fatigue and muscle weakness, reduced extracellular fluid volume, and decreased cardiac function. Although recombinant GH therapy represents the current standard of care for GH-deficient patients, it is not ideal due to adverse effects associated with long-term therapies (Gibney et al., 1999). On the other hand, GH secretagogue has shown marked improvements over the traditional remedies by enhancing pulse amplitudes and integrated hormone production in elderly subjects (Huhn et al., 1993;Aloi et al., 1994;Chapman et al., 1997).CP-424391 belongs to the pyrazolidine-piperidine class of compounds currently being developed as an orally active GH secretagogue for the treatment of growth hormone-compromised states. Its pharmacological mechanism of action is the elevation of circulating GH levels by stimulation of GH release from the pituitary gland (Pan, 2000). The objective of the present study was to investigate the metabolic fate and disposition of CP-...

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