ABSTRACT:The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a partial agonist of the nicotinic acetylcholine receptor for the treatment of tobacco addiction, was examined in rats, mice, monkeys, and humans after oral administration of [ 14 C]varenicline. In the circulation of all species, the majority of drug-related material was composed of unchanged varenicline. In all four species, drug-related material was primarily excreted in the urine. A large percentage was excreted as unchanged parent drug (90, 84, 75, and 81% of the dose in mouse, rat, monkey, and human, respectively). Metabolites observed in excreta arose via N-carbamoyl glucuronidation and oxidation.These metabolites were also observed in the circulation, in addition to metabolites that arose via N-formylation and formation of a novel hexose conjugate. Experiments were conducted using in vitro systems to gain an understanding of the enzymes involved in the formation of the N-carbamoylglucuronide metabolite in humans. N-Carbamoyl glucuronidation was catalyzed by UGT2B7 in human liver microsomes when incubations were conducted under a CO 2 atmosphere. The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation.

ABSTRACT:The Michaelis constant (K M ) for cytochrome P450-mediated drug biotransformation reactions can be an important parameter in understanding the potential for a drug to exhibit saturable metabolism in vivo and nonlinear dose-exposure relationships. K M values were measured for several drug biotransformation reactions using recombinant heterologously expressed human enzymes. These determinations were made using an approach of monitoring substrate loss ("in vitro t 1/2 " method) at multiple substrate concentrations, with the objective of comparing K M values determined by this approach with K M values determined using the conventional approach of measuring product formation rates at several substrate concentrations. The reactions examined were CYP2C9-catalyzed diclofenac 4-hydroxylation, CYP2D6-catalyzed dextromethorphan O-demethylation and thioridazine S-oxidation, CYP2C19-catalyzed imipramine N-demethylation, CYP3A4-cata- The determination of enzyme kinetic parameters, K M , V max , and CL int Ј , for cytochrome P450-catalyzed reactions is an important aspect in drug discovery and development (Obach, 2001). In drug discovery, these in vitro data can be used in compound design to optimize the human pharmacokinetic behavior of new chemical entities. Such parameters can be used to predict human clearance prior to human administration (Iwatsubo et al., 1996;Obach et al., 1997;Houston and Carlile, 1997;Lave et al., 1999). In drug development, enzyme kinetic data for drug biotransformation reactions can be used to better understand the mechanism of clearance of new chemical entities in humans to assess potential determinants of interindividual variability in pharmacokinetics such as drug-drug interactions, genetic polymorphisms of drug clearance mechanisms, and nonlinear dose-exposure relationships.The K M value (Michaelis constant) is a primary descriptor of the enzyme kinetic behavior of a biotransformation reaction. In simple kinetic systems, it represents the substrate concentration that will yield a reaction velocity that is half of the theoretical maximum reaction velocity that would occur at an infinite substrate concentration (V max ). In a practical sense, the K M value can be reflective of the potential of a drug to saturate, or partially saturate, an enzyme involved in its metabolic clearance. The lower the K M value, the greater the possibility that the drug concentrations attained in vivo will saturate the metabolic clearance pathway. When this phenomenon occurs, it can be problematic because the drug will exhibit a nonlinear, supraproportional dose-exposure relationship (Ludden, 1991). For drugs with low-therapeutic indices, small increases in dose can potentially introduce toxicity as drug concentrations in vivo will increase to a much greater extent than that expected from the increase in dose. Such pharmacokinetic behavior has been observed for numerous compounds spanning several therapeutic indications, some of which are listed in Table 1. The K M value will not solely be responsible for supra...

The pharmacokinetics of ezlopitant were determined in the rat, gerbil, guinea pig, ferret, dog and monkey after intravenous and oral administration. In general, ezlopitant is marked by high clearance values that approach or exceed hepatic blood flow values, moderate to high values for steady-state volume of distribution (3. 9-28 L/kg), and terminal phase half-life values ranging from 0.6 h in the guinea pig to 7.7 h in the rat. Oral bioavailability ranged from <0.2% (guinea pig) to 28% (dog). Data from portal vein cannulated dogs suggested that 37% of an oral dose of ezlopitant enters the portal vein as an unchanged drug in this species. Ezlopitant is metabolized to two pharmacologically active metabolites, an alkene (CJ-12 458) and a benzyl alcohol (CJ-12 764). After administration of the parent compound, CJ-12 764 was found in greater abundance than CJ-12 458 in all species examined. Ezlopitant and CJ-12 458 were highly protein bound in plasma (or serum), whereas the protein binding of CJ-12 764 was somewhat lower. Measurement of the kinetics of ezlopitant, CJ-12 458 and CJ-12 764 in the cerebrospinal fluid (CSF) of dogs demonstrated that all three compounds can partition into the CSF, and thereby, be capable of contributing to centrally mediated pharmacological effects. Thus, these data suggest that the pharmacological activity exhibited by ezlopitant in preclinical species in vivo is likely a result of the parent compound plus the active metabolites. Furthermore, the contributions of ezlopitant and the active metabolites to pharmacological activity probably varies with the identity of the model species, as well as the dose and route of ezlopitant administration.

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