This article is available online at http://dmd.aspetjournals.org ABSTRACT:Uridine diphosphate glucuronosyltransferases (UGTs) catalyze the glucuronidation of a wide range of xenobiotics and endogenous substrates. However, there is a lack of information concerning the response of human UGTs to inducers, and this observation prompted the current investigation. The glucuronidation of estradiol (3-and 17-positions), naphthol, propofol, and morphine (3-and 6-positions) was assessed against a battery of recombinant human UGTs to determine selective glucuronidation reactions for induction studies. The potential induction of the glucuronidation of estradiol at the 3-position, naphthol, propofol, and morphine at the 3-position was subsequently investigated in cultured primary human hepatocytes against a range of prototypic inducers including dexamethasone, 3-methylcholanthrene (3-MC), phenobarbital, rifampicin, and omeprazole. Treatment with 3-MC induced estradiol-3-glucuronidation (up to 2.5-fold) in four of five donors investigated. Statistically significant increases in naphthol glucuronidation (up to 1.7-fold) were observed following treatment with carbamazepine. UGT1A9-mediated propofol glucuronidation was induced by phenobarbital (up to 2.2-fold) and rifampicin (up to 1.7-fold). However, treatment with ␣-naphthoflavone and tangeretin resulted in a decrease in propofol glucuronidation (30% of control values). Statistically significant induction of morphine-3-glucuronidation was observed in at least three donors following treatment with phenobarbital, rifampicin, and carbamazepine. Each UGT isoform investigated displayed a distinct induction profile. Although statistically significant increases in glucuronidation were observed for each reaction studied, the level of induction was less than that observed for CYP1A2 or CYP3A4 and exhibited a large interdonor variability. The clinical relevance of the induction responses obtained in this study is unclear.

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In the studies reported here, the ability of atomoxetine hydrochloride (Strattera) to inhibit or induce the metabolic capabilities of selected human isoforms of cytochrome P450 was evaluated. Initially, the potential of atomoxetine and its two metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit the metabolism of probe substrates for CYP1A2, CYP2C9, CYP2D6, and CYP3A was evaluated in human hepatic microsomes. Although little inhibition of CYP1A2 and CYP2C9 activity was observed, inhibition was predicted for CYP3A (56% predicted inhibition) and CYP2D6 (60% predicted inhibition) at concentrations representative of high therapeutic doses of atomoxetine. The ability of atomoxetine to induce the catalytic activities of CYP1A2 and CYP3A in human hepatocytes was also evaluated; however, atomoxetine did not induce either isoenzyme. Based on the potential of interaction from the in vitro experiments, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metabolizer subjects and CYP3A (midazolam) in CYP2D6 poor metabolizer subjects. Single-dose pharmacokinetic parameters of desipramine (single dose of 50 mg) were not altered when coadministered with atomoxetine (40 or 60 mg b.i.d. for 13 days). Only modest changes (approximately 16%) were observed in the plasma pharmacokinetics of midazolam (single dose of 5 mg) when coadministered with atomoxetine (60 mg b.i.d. for 12 days). Although at high therapeutic doses of atomoxetine inhibition of CYP2D6 and CYP3A was predicted, definitive in vivo studies clearly indicate that atomoxetine administration with substrates of CYP2D6 and CYP3A does not result in clinically significant drug interactions.Atomoxetine hydrochloride (Strattera; formerly known as tomoxetine hydrochloride) is known chemically as (Ϫ)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine 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) and is used clinically for the treatment of attention-deficit/hyperactivity disorder in children, adolescents, and adults.Atomoxetine is rapidly and completely absorbed after oral administration . The plasma pharmacokinetics of atomoxetine are linear over the recommended therapeutic dosing range (0.5-1.4 mg/kg) with proportional increases in both mean atomoxetine maximum plasma concentration (C max ) and area under the plasma concentration time curve (AUC) with increasing dose . Atomoxetine is predominantly metabolized by CYP2D6 (Ring et al., 2002); therefore, its pharmacokinetics and metabolism are influenced by the polymorphic expression of this enzyme (Farid et al., 1985;Sauer et al., 2003). As a result, the systemic clearance values of atomoxetine seem to be distributed in a bimodal manner. The enzymatic activity of CYP2D6 is regulated by a genetic polymorphism resulting in two major populations of individuals with either active met...

On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN. The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN. For the approval of the SC dosing regimen (400 mg dose QW for four doses, then 200 mg QW thereafter), efficacy was supported solely by pharmacokinetics (PK) modeling and simulation which estimated a matched steady state average concentration and higher trough concentrations for the SC administration route, for bridging to the efficacy of IV belimumab in adults with LN. The safety and immunogenicity profile of the SC administration route has been assessed in the SLE studies. In a population PK analysis, higher proteinuria was associated with greater belimumab clearance and lower belimumab exposure. In an exposure response analysis, the efficacy of belimumab as evaluated by renal response was mainly driven by patients with lower proteinuria at baseline regardless of other baseline characteristics (e.g. baseline renal function, renal biopsy classification), induction therapies, or belimumab exposure levels (within 10 mg/kg dosing regimen), etc. However, post hoc analyses showed that belimumab had activity in LN patients with higher proteinuria at baseline. There is no adequate information to suggest that a higher dose would provide additional benefit for patients with lower exposure (e.g. higher proteinuria).