Internal rotation processes inendo-cis-N-(o-tolyl)bicyclo[2.2.1]heptene-2,3-dicarboximide and its oxidation products

Campos, Marcos Pery Amaral; Bergter, Lothar; Silva, Carlos Henrique Tomich de Paula da; Seidl, Peter Rudolf

doi:10.1002/(sici)1097-458x(199904)37:4<317::aid-mrc444>3.0.co;2-7

Cited by 2 publications

(1 citation statement)

References 25 publications

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“…The glucuronide ring is linked to the imidazole ring with covalent nitrogen-carbon bond, a type of chemical bond that is known to undergo atropoisomerism. Atropoisomerism (Schantl, 1995;Campos et al, 1999;Voitenko et al, 2002) is a type of stereoisomerism that may arise in systems where free rotation around a single covalent bond is sufficiently impeded to allow different stereoisomers to be isolated. For metabolites M1 and M2, we assumed that the glucuronide ring located on atom N (2) of the imidazole ring underwent a restricted rotational motion around the nitrogen-carbon bond.…”

Section: In Vitro Direct N-glucuronidation Of Midazolammentioning

confidence: 99%

Contribution of the N-Glucuronidation Pathway to the Overall in Vitro Metabolic Clearance of Midazolam in Humans

Klieber¹,

Hugla²,

Ngo³

et al. 2008

Drug Metabolism and Disposition

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ABSTRACT:Midazolam (MDZ) is one of the most commonly used in vivo and in vitro CYP3A4 probe substrates for drug-drug interactions (DDI) studies. The major metabolic pathway of MDZ in humans consists of the CYP3A4-mediated 1-hydroxylation followed by urinary excretion as 1-O-glucuronide derivative. In the present study, following incubation of MDZ with human liver microsomes supplemented with UDP-glucuronic acid, two major high-performance liquid chromatography (HPLC) peaks were isolated. HPLC and liquid chromatography/tandem mass spectrometry analyses identified these two metabolites as quaternary direct N-glucuronides of MDZ, thus revealing an additional metabolic pathway for MDZ. Because a large number of currently available drugs and future drugs will be metabolized by the members of the CYP3A subfamily, the potential for drug-drug interaction (DDI) is substantial. DDIs involving the inhibition and induction of CYP3A4 are of great scientific and clinical relevance. Indeed, drugs with potent CYP3A4 inhibitory properties have been implicated in significant CYP3A4-mediated DDIs. Interactions of the benzodiazepines with the azole antifungal agents and especially the inhibition of CYP3A-mediated midazolam (MDZ) metabolism by ketoconazole have been widely studied. Concomitant administration of both drugs results in large, variable, and highly significant increases (5-16-fold) in MDZ exposure, depending on the dose regimen of ketoconazole used. Table 1 summarizes available clinical data on the effects of ketoconazole on MDZ plasma levels following p.o. or i.v. administration of MDZ.MDZ is a short-acting water-soluble imidazobenzodiazepine (Fig. 1) extensively used in clinical practice mainly for induction and maintenance of anesthesia, sedation for diagnostic and therapeutic procedures, and also as an oral hypnotic agent (Reves et al., 1985). MDZ is a well known CYP3A substrate because its metabolism has been the focus of many in vitro investigations (Fabre et al., 1988b;Kronbach et al., 1989;Wrighton and Ring, 1994;Ghosal et al., 1996; Maenpaa et al., 1998;Hosea et al., 2000;Wang et al., 2000). MDZ biotransformation is mediated by at least three different CYP3A isoenzymes: CYP3A4, CYP3A5, and CYP3A7 (Gorski et al., 1994;Kuehl et al., 2001). Because CYP3A7 is principally expressed in fetal tissues, CYP3A4 and CYP3A5 represent the main cytochrome P450 (P450) isoforms in adult liver and intestine (Guengerich, 1995).MDZ biotransformation yields two primary hydroxylated metabolites: 1Ј-hydroxy-MDZ (1Ј-OH-MDZ) and 4-hydroxy-MDZ. 1Ј-OH-MDZ represents the main metabolite because it accounts for 95% of net intrinsic clearance of MDZ in human liver microsomes (von Article, publication date, and citation information can be found at

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Section: In Vitro Direct N-glucuronidation Of Midazolammentioning

confidence: 99%