The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

No abstract

ABSTRACT:Thirty-two structurally diverse drugs used for the treatment of various conditions of the central nervous system (CNS), along with two active metabolites, and eight non-CNS drugs were measured in brain, plasma, and cerebrospinal fluid in the P-glycoprotein (P-gp) knockout mouse model after subcutaneous administration, and the data were compared with corresponding data obtained in wild-type mice. Total brain-to-plasma (B/P) ratios for the CNS agents ranged from 0.060 to 24. Of the 34 CNS-active agents, only 7 demonstrated B/P area under the plasma concentration curve ratios between P-gp knockout and wild-type mice that did not differ significantly from unity. Most of the remaining drugs demonstrated 1.1-to 2.6-fold greater B/P ratios in P-gp knockout mice versus wild-type mice. Three, risperidone, its active metabolite 9-hydroxyrisperidone, and metoclopramide, showed marked differences in B/P ratios between knockout and wild-type mice (6.6-to 17-fold). Differences in B/P ratios and cerebrospinal fluid/ plasma ratios between wild-type and knockout animals were correlated. Through the use of this model, it appears that most CNSactive agents demonstrate at least some P-gp-mediated transport that can affect brain concentrations. However, the impact for the majority of agents is probably minor. The example of risperidone illustrates that even good P-gp substrates can still be clinically useful CNS-active agents. However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect.Active transport mechanisms as determinants of drug absorption, distribution, and clearance have been the focus of considerable research effort over the past decade. Of the numerous transporter proteins recently investigated, the one for which the greatest amount of knowledge exists is P-glycoprotein (MDR1). Originally described as a transporter involved in imparting drug resistance to tumor cells, P-glycoprotein has been demonstrated to be important in reducing absorption of drugs from the intestinal lumen, in active secretion of drugs into urine and bile, and in extrusion of drugs from vital organs such as the brain and reproductive tissues (Troutman et al., 2002). As such, P-glycoprotein-mediated transport has become an important issue in the discovery and development of new drugs. For example, new compounds that are promising with regard to target receptor/ enzyme activity can be severely hampered in their ability to elicit pharmacological effects in vivo should they be good substrates for P-glycoprotein, especially if the route of administration is intended to be oral or the target tissues is one rich in P-glycoprotein activity. Furthermore, the potential for drug-drug interactions arises in the event that the P-glycoprotein substrate is coadministered with another agent that can inhibit P-glycoprotein.Several models have been developed to assess drugs as P-glycoprotein substrates. In vitro models have included the Caco...

No abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a twostep incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estimated by varying the time of preincubation as well as the concentration of inhibitor.

Oral bioavailability (F) is a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh). In this study, using a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans, an analysis of the interrelation of physicochemical properties and the individual parameters was carried out in order to define the physicochemical space for optimum human oral bioavailability. Trend analysis clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. These trends were due to a combination of effects of the properties on Fa and first-pass elimination (Fg and Fh). Higher MW significantly impacted Fa, while Fg and Fh decreased with increasing lipophilicity. Parabolic trends were observed for bioavailability with polar descriptors. Interestingly, RB has a negative effect on all three parameters, leading to its pronounced effect on bioavailability. In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination. This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability.

Kidney plays an important role in the elimination of drugs, especially with low or negligible hepatic clearance. An analysis of the interrelation of physicochemical properties and the human renal clearance for a data set of 391 drugs or compounds tested in humans is presented. The data set indicated that lipophilicity shows a negative relationship while polar descriptors show a positive relationship with renal clearance. Analysis of net secreted and net reabsorbed subsets revealed that hydrophilic ionized compounds are probable compounds to show net secretion and a possible drug-drug interaction due to their likely interaction with uptake transporters and inherent low passive reabsorption. The physicochemical space and renal clearance were also statistically analyzed by therapeutic area. In conclusion, ionization state, lipophilicity, and polar descriptors are found to be the physicochemical determinants of renal clearance. These fundamental properties can be valuable in early prediction of human renal clearance and can aid the chemist in structural modifications to optimize drug disposition.

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.