ABSTRACT:The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(؊)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of 14 C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n ‫؍‬ 4) and poor metabolizer (PM; n ‫؍‬ 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 h, whereas in PM subjects the majority of the dose was excreted by 72 h. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, and N-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t 1/2 ‫؍‬ 62 h) compared with EM subjects (t 1/2 ‫؍‬ 18 h). In EM subjects, atomoxetine (t 1/2 ‫؍‬ 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t 1/2 ‫؍‬ 7 h) were the principle circulating species, whereas atomoxetine (t 1/2 ‫؍‬ 20 h) and Ndesmethylatomoxetine (t 1/2 ‫؍‬ 33 h) were the principle circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 4-hydroxyatomoxetine.Atomoxetine hydrochloride (LY139603; formerly known as tomoxetine hydrochloride) is known chemically as (Ϫ)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride. Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other monoamine transporters or receptors (Wong et al., 1982;Gehlert et al., 1993). Atomoxetine is under development as a therapeutic agent for the treatment of attention deficit/hyperactivity disorder in children, adolescents, and adults.Atomoxetine is predominantly metabolized by CYP2D6 (Ring et al., 2002); therefore, its single and multiple dose pharmacokinetics are influenced by the polymorphic expression of this enzyme (Farid et al., 1985). As a result, the pharmacokinetics of atomoxetine appear to have a bimodal distribution with two distinct populations. The enzymatic activity of CYP2D6 is determined by a genetic polymorphism (Evans et al., 1980;Steiner et al., 1988), and is an important source of intersubject variability in metabolism for a number of drugs, including debrisoquine, desipramine, and dextromethorphan (Wolf and Smith, 1999). Mutations or deletion of the CYP2D6 gene results in a mino...

Platelet aggregation and activation are serious concerns for patients who undergo percutaneous coronary intervention and stent placement. The underlying mechanism of platelet aggregation is mediated through two G protein-coupled P2 receptors, P2Y 1 and P2Y 12 (Gachet, 2001). P2Y 1 activation leads to a transient aggregation, whereas P2Y 12 activation maintains a sustained aggregation. To reduce platelet aggregation, the development of P2Y 12 -selective inhibitors has yielded the thienopyridine prodrugs, which include ticlopidine, clopidogrel (structures available in Farid et al., 2008), and prasugrel ( Fig. 1), a novel thienopyridine currently in clinical development.Although the active metabolites for prasugrel and clopidogrel have equipotency at the P2Y 12 receptor in vitro (Sugidachi et al., 2007), p.o. administered prasugrel is 10 and 100 times more effective on an equal-dose basis in inhibiting platelet aggregation than clopidogrel and ticlopidine, respectively (Niitsu et al., 2005). Clopidogrel and prasugrel differ markedly in the biotransformation pathways leading to their activation. Prasugrel (Fig. 1) has a single dominant metabolic pathway leading to the active metabolite (Farid et al., 2007a). However, clopidogrel has two competing metabolic pathways for the parent compound, with the major pathway leading to the formation of an inactive metabolite, clopidogrel carboxylic acid derivative (Caplain et al., 1999). The clopidogrel carboxylic acid derivative is formed through ester hydrolysis by the human carboxylesterase (hCE) 1 (Tang et al., 2006). The minor pathway in clopidogrel metabolism yielding the active metabolite requires two sequential steps of cytochrome P450 (P450) biotransformation (Kurihara et al., 2005), whereas prasugrel bioactivation requires the hydrolysis of the ester and then oxidation of the formed thiolactone, R-95913 (Farid et al., 2007a) (Fig. 1), to form the active metabolite of prasugrel. The oxidation of R-95913 has been shown to be mediated by several P450 enzymes but primarily by CYP3A and CYP2B6 (Rehmel et al., 2006).The carboxylesterases are a multigene family that hydrolyze compounds containing an ester, amide, or thioester linkage. Carboxylesterases are broadly expressed throughout the body with two major Article, publication date, and citation information can be found at

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ABSTRACT:These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(؊)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F ‫؍‬ 4%) compared with the high oral bioavailability in dog (F ‫؍‬ 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and Ndemethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.

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The purpose of this study was to examine whether atomoxetine plasma concentration predicts attention-deficit/hyperactivity disorder (ADHD) or oppositional defiant disorder (ODD) response. This post-hoc analysis assessed the relationship between atomoxetine plasma concentration and ADHD and ODD symptoms in patients (with ADHD and comorbid ODD) aged 6–12 years. Patients were randomly assigned to atomoxetine 1.2 mg/kg/day (n = 156) or placebo (n = 70) for 8 weeks (Study Period II). At the end of 8 weeks, ODD non-remitters (score >9 on the SNAP-IV ODD subscale and CGI-I > 2) with atomoxetine plasma concentration <800 ng/ml at 2 weeks were re-randomized to either atomoxetine 1.2 mg/kg/day or 2.4 mg/kg/day for an additional 4 weeks (Study Period III). ODD remitters and non-remitters with plasma atomoxetine ≥800 ng/ml remained on 1.2 mg/kg/day atomoxetine for 4 weeks. Patients who received atomoxetine, completed Study Period II, and entered Study Period III were included in these analyses. All the groups demonstrated improvement on the SNAP-IV ODD and ADHD-combined subscales (P < .001). At the end of Study Periods II and III, ODD and ADHD improvement was significantly greater in the remitter group compared with the non-remitter groups. Symptom improvement was numerically greater in the non-remitter (2.4 mg/kg/day compared with the non-remitter 1.2 mg/kg/day) group. Atomoxetine plasma concentration was not indicative of ODD and ADHD improvement after 12 weeks of treatment. ADHD and ODD symptoms improved in all the groups with longer duration on atomoxetine. Results suggest atomoxetine plasma concentration does not predict ODD and ADHD symptom improvement. However, a higher atomoxetine dose may benefit some patients.

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Cephaloridine (Cld) is a nephrotoxic cephalosporin antibiotic. The intracellular biochemical changes that occur leading to Cld-induced nephrotoxicity may involve lipid peroxidation and/or mitochondria1 injury. The purpose of this report was to examine and correlate the biochemical changes induced by Cld in vivo and in vitro with the observed pathological changes in an attempt to understand better the mechanisms of@-lactaminduced nephrotoxicity. Cld treatment (500 mg/kg sc) caused elevations in blood urea nitrogen and decreases in the accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices.Histopathological alterations, characterized by individual cell necrosis of tubular epithelial cells, were first seen 6 hr after treatment in the pars recta of the outer stripe of the medulla. Ultrastructural alterations involved the straight (S, and S,) segments of the proximal tubules. Mitochondria1 morphology was, for the most part, unaffected by Cld exposure. Cld did not cause any significant changes in tissue malondialdehyde (MDA)content in vivoat any ofthe timepointsexamined, but it didcauseadepletion ofGSH toapproximately 40% of control by 1 hr after dosing that recovered toward control by 6 hr. Significant changes were observed in renal ATP content beginning at 6 hr after treatment; however, this change mirrored the onset of histological evidence of necrosis. In isolated tubules in vitro, the onset ofglutathione (GSH) depletion and MDA formation clearly preceded lactate dehydrogenase (LDH) leakage, whereas ATP depletion was a mirror image of cell death. These data demonstrate that isolated proximal tubules in vitro are a reasonable model for Cld nephrotoxicity in rivo. Cld-induced mitochondria1 alterations leading to ATP depletion and cell injury were not observed in this study.