Metabolism and Disposition of Calcimimetic Agent Cinacalcet HCL in Humans and Animal Models

Abstract

ABSTRACT:The metabolism and disposition of calcimimetic agent cinacalcet HCl was examined after a single oral administration to mice, rats, monkeys, and human volunteers. In all species examined, cinacalcet was well absorbed, with greater than 74% oral bioavailability of cinacalcet-derived radioactivity in monkeys and humans. In rats, cinacalcet-derived radioactivity was widely distributed into most tissues, with no marked gender-related differences. In all animal models examined, radioactivity was excreted rapidly via both hepatobiliary and urinary routes. In humans, radioactivity was cleared primarily via the urinary route (80%), with 17% excreted in the feces. Cinacalcet was not detected in the urine in humans. The primary routes of metabolism of cinacalcet were N-dealkylation leading to carboxylic acid derivatives (excreted in urine as glycine conjugates) and oxidation of naphthalene ring to form dihydrodiols (excreted in urine and bile as glucuronide conjugates). The plasma radioactivity in both animals and humans was primarily composed of carboxylic acid metabolites and dihydrodiol glucuronides, with <1% circulating radioactivity accounting for the unchanged cinacalcet. Overall, the circulating and excreted metabolite profile of cinacalcet in humans was qualitatively similar to that observed in preclinical animal models.Calcimimetic agents act as positive allosteric modulators of the calcium receptor located on the surface of the parathyroid cells (Nemeth et al., 1998;Cohen and Silverberg, 2002). Cinacalcet HCl (AMG 073; hereinafter referred to as cinacalcet), a calcimimetic agent, acts on the calcium-sensing receptor of the parathyroid, the principal regulator of parathyroid hormone release, to increase its sensitivity to activation by extracellular calcium, thus decreasing parathyroid hormone. The clinical efficacy of cinacalcet has been demonstrated in several studies in subjects with secondary hyperparathyroidism (Drueke et al., 2001;Goodman et al., 2002;Quarles et al., 2003).Nonclinical biodisposition studies (ADME) of a new chemical entity play a critical role in its initial selection as well as in its subsequent clinical development. Biodisposition studies provide important information regarding the absorption of the drug from the site of administration, distribution of the drug-related material into the target tissues, metabolic pathways to which the drug is subject, and the eventual excretion of the drug-related material from the body (Campbell, 1994;Caldwell et al., 1995;Miwa, 1995). The information generated from these studies is helpful in understanding the outcomes of the safety studies (e.g., toxic and reactive metabolites, covalent binding to macromolecules, species-specific toxicity) and in some instances the outcomes of pharmacology studies (e.g., the presence of active metabolites, distribution into target organ) (Wiltshire et al., 1997;Bischoff et al., 1998;Mutlib et al., 2000). These studies are also immensely helpful in understanding the potential behavior of a drug candidate in humans...

Propiedades Fotoquimicas De Farmacos Que Contienen El Cromoforo Naftaleno en Medios Microheterogeneos.

“…In a first stage, a Monte-Carlo approach, using the GULP code [2], has been used in order to explore a large conformational space of binding sites of -separately-CIN and PPN at HAAG. Starting with experimental location of some drugs [1], a large area of the protein around those binding sites has been explored in order to find stable binding sites for CIN and PPN.…”

“…36 Por otra parte, la ASB, está constituida por 583 aminoácidos. 37 Las albúminas ASH y ASB son muy similares estructuralmente, de hecho la secuencia peptídica de ASB presenta una similitud del 76% …”

“…The emission spectrum of CINH þ in PBS was measured at 290 nm (A 290 = 0.1), under air. As the reported pK a value of CIN is 8.72, 37 basically all the compound is protonated under the employed experimental conditions (pH 7.4). Parallel measurements were made in the presence of equimolar amounts of HSA, and a control experiment was performed with the protein alone ( Figure 6 and Table 2).…”

“…1 The interaction of SAs with small molecules (i.e., drugs, metabolites, or fatty acids) has been widely investigated using different techniques to gain insight into the mechanism of transport processes and to establish the structural basis for designing new therapeutic agents. 2 For human serum albumin (HSA), Sudlow and coworkers found two primary high-affinity binding sites, called site I (warfarin) and site II (indole-benzodiazepine), with association constants in the range of 10 4…”

“…These microheterogeneous systems have been employed as models to study the photochemical behavior of a variety of drugs and its dependence on the nature of the media. [1][2][3][4] In this context, mixed micelles (MM) made of phospholipids and bile salts have attracted increasing attention as nanocarriers in pharmaceutical formulations due to their important advantages, such as enhanced stability and reduced toxicity. [5][6][7][8][9] In fact, MM However, most of them are based on indirect measurements and do not inform on the accessibility of the drugs inside biomimetic microenvironments.…”