Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase

Lake, Brian G.; Ball, S.; Kao, J.; Renwick, A.B.; Price, Roger J.; Scatina, JoAnn

doi:10.1080/00498250210158915

Cited by 81 publications

(37 citation statements)

References 15 publications

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“…The previously mentioned substrate zaleplon, a sedative drug used primarily for the treatment of insomnia, is a nonbenzodiazepine hypnotic that is cleared primarily by AOX (Lake et al, 2002). In addition, famciclovir, an antiviral prodrug used primarily to treat herpes virus infection is activated by AOX to its active 6-oxo form, penciclovir (Clarke et al, 1995;Rashidi et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…To date only one pharmacokinetic drug interaction due to the inhibition of AOX, between cimetidine and zaleplon, has been discovered (Lake et al, 2002). Predicting drug interactions with AOX is also relatively more difficult than with cytochrome P450 primarily because animal models are poor predictors of human AOX activity owing to the marked interspecies variation of expression levels and number of isoforms (Garattini and Terao, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

Barr

Jones

2011

Drug Metab Dispos

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ABSTRACT:During the course of our research efforts to understand the kinetics of human aldehyde oxidase as a xenobiotic-clearing enzyme, we investigated the effect of eight different inhibitors on the oxidation of the probe substrate phthalazine. Saturation kinetic parameters for phthalazine oxidation in human liver cytosol were found to be the following:Inhibitory potency of the inhibitors tested ranged from 0.1 to 5 M. Of the eight different inhibitor compounds tested, seven were observed to inhibit through a mixed mode and one through a strictly competitive mode. A ratio of the K ii and K is values was used to assess the relative competitiveness of each inhibitor. For the mixed inhibitors, the mode of inhibition varied from mostly uncompetitive to predominantly competitive (K ii /K is values ranging from 0.1 to 15). The implications for potential drug-drug interactions and inhibition mechanism are discussed. We found two inhibitors, clozapine and chlorpromazine, that have a moderate predicted risk of drug-drug interactions based on the K i value relative to the inhibitor concentration in human plasma, having a calculated [I]/K i value of 0.4 and 0.8, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

Barr

Jones

2011

Drug Metab Dispos

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“…A notable example is the recently introduced azaheterocyclic hypnotic agent, zaleplon (Kawashima et al, 1999;Lake et al, 2002), in which aldehyde oxidase generates the major metabolite 5-oxozaleplon as well as the corresponding 5-oxo analog of the N-dealkylated metabolite of zaleplon. Also, the bioactivation of famciclovir to the active antiviral agent penciclovir requires aldehyde oxidase-mediated metabolism (Clarke et al, 1995;Rashidi et al, 1997).…”

mentioning

confidence: 99%

Potent Inhibition of Human Liver Aldehyde Oxidase by Raloxifene

2004

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The selective estrogen receptor modulator, raloxifene, has been demonstrated as a potent uncompetitive inhibitor of human liver aldehyde oxidase-catalyzed oxidation of phthalazine, vanillin, and nicotine-⌬1(5)-iminium ion, with K i values of 0.87 to 1.4 nM. Inhibition was not time-dependent. Raloxifene has also been shown to be a noncompetitive inhibitor of an aldehyde oxidase-catalyzed reduction reaction of a hydroxamic acid-containing compound, with a K i of 51 nM. However, raloxifene had only small effects on xanthine oxidase, an enzyme related to aldehyde oxidase. In addition, several other compounds of the same therapeutic class as raloxifene were examined for their potential to inhibit aldehyde oxidase. However, none were as potent as raloxifene, since IC 50 values were orders of magnitude higher and ranged from 0.29 to 57 M. In an examination of analogs of raloxifene, it was shown that the bisphenol structure with a hydrophobic group on the 3-position of the benzthiophene ring system was the most important element that imparts inhibitory potency. The relevance of these data to the mechanistic understanding of aldehyde oxidase catalysis, as well as to the potential for raloxifene to cause drug interactions with agents for which aldehyde oxidase-mediated metabolism is important, such as zaleplon or famciclovir, is discussed.Aldehyde oxidase is an enzyme involved in the metabolism of drugs and other xenobiotics that possess aldehyde and azaheterocyclic substituents, among others (Beedham, 2002). It is a member of a family of enzymes referred to as molybdenum cofactor-containing enzymes that also includes xanthine oxidase, due to the presence of the unique molybdopterin prosthetic group. It is present in the liver, as well as some other tissues of humans and other mammalian species such as the rat, guinea pig, monkey, and rabbit. Aldehyde oxidase converts aldehydes to carboxylic acids and azaheterocyclic compounds to lactams using molecular oxygen as an electron acceptor. It can also catalyze reduction reactions of some drugs, with the drug that is reduced replacing oxygen as the electron acceptor.Drugs for which aldehyde oxidase plays the predominant role in metabolic clearance are few. A notable example is the recently introduced azaheterocyclic hypnotic agent, zaleplon (Kawashima et al., 1999;Lake et al., 2002), in which aldehyde oxidase generates the major metabolite 5-oxozaleplon as well as the corresponding 5-oxo analog of the N-dealkylated metabolite of zaleplon. Also, the bioactivation of famciclovir to the active antiviral agent penciclovir requires aldehyde oxidase-mediated metabolism (Clarke et al., 1995;Rashidi et al., 1997). Famciclovir is converted to the 6-oxo metabolite, which undergoes deesterification to penciclovir; also, the deesterified analog of famciclovir, 6-deoxypenciclovir, is oxidized by aldehyde oxidase to the active compound. Although it is not frequently involved in initial pathways of metabolism of drugs, ...

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“…The elimination of the tracer from the mouse body was attained via two routes; the first one is the kidneys through which the main radioactivity was eliminated (3.6%, 9.3%, 12.8%, and 4.6% at 5, 30, 60, and 120 minutes, respectively). The second route of tracer elimination was the liver, the total radioactivities detected in this excretory system were 2.8%, 6.1%, 7.3%, and 2.9% at 5, 30, 60, and 120 minutes, respectively) (Lake, Ball, Kao, Renwick, Price, & Scatina, 2002). In respect to the radioactivity taken up by the brain and that in the blood per gram tissues (target to non-target), it is concluded that the ratio increased with time passes and reached to its maximum value of 2.3 at 120 minutes post injection.…”

Section: Biodistributionmentioning

confidence: 99%

Radioiodination of Zaleplon and Its in-vivo Biologic Behavior in Mice: An Imaging Probe for Brain

Amin¹,

Soliman²,

El-Aziz³

et al. 2013

IJC

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The hypnotic zaleplon displays novel receptor selectivity different from other benzodiazepine receptor ligands in clinical use. Zaleplon was successfully labeled with iodine-125 via electrophilic substitution reaction producing 125 I-Zaleplon tracer. This reaction proceeds well in acidic pH of value equal to 4, due to the solubility of the Zaleplon in this acidic pH value. Chloramine-T (CAT) was used as oxidizing agent, at low amount of (CAT) (25-50g) the radiochemical yield of the labeled compound was low (80%) while at 200 g, an optimum yield (97%) was obtained.Heating the reaction mixture to 40 C for 15 min was recommended to get a yield more than 97%, but heating for longer time causes a decomposition of the labeled Zaleplon. The in-vitro stability of 125 I-Zaleplon was determined along 24 hours; the data confirms that 125 I-Zaleplon tracer was stable along eight hours without the detection of any by-products in the reaction mixture. The biodistribution data of the labeled Zaleplon shows rapid blood clearance passes through the blood brain barrier (BBB) and the activity detected in the brain exceeds 4.4% at 1 h post injection.

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Metabolism of zaleplon by human liver: evidence for involvement of aldehyde oxidase

Cited by 81 publications

References 15 publications

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

Inhibition of Human Liver Aldehyde Oxidase: Implications for Potential Drug-Drug Interactions

Potent Inhibition of Human Liver Aldehyde Oxidase by Raloxifene

Radioiodination of Zaleplon and Its in-vivo Biologic Behavior in Mice: An Imaging Probe for Brain

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