Zaleplon pharmacokinetics and absolute bioavailability

Rosen, Amy; Fournié, Philippe; Darwish, Mona; Danjou, Philippe; Troy, Steven

doi:10.1002/(sici)1099-081x(199904)20:3<171::aid-bdd169>3.0.co;2-k

Cited by 81 publications

(30 citation statements)

References 5 publications

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“…Zaleplon attains peak concentration (C max ) within 1.1 h (t max ) approximately after administration, with terminal elimination half life of 1 hour (5). Cmax and area under the plasma concentration-time curve (AUC) both exhibit linear dose proportionality at doses up to 60 mg well above the 10 mg therapeutic dose (6,7).…”

Section: Zaleplon (supporting

confidence: 59%

Development and Characterization of Zaleplon Solid Dispersion Systems: A Technical Note

Waghmare¹,

Pore²,

Kuchekar³

2008

AAPS PharmSciTech

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Section: Zaleplon (supporting

confidence: 59%

Development and Characterization of Zaleplon Solid Dispersion Systems: A Technical Note

Waghmare¹,

Pore²,

Kuchekar³

2008

AAPS PharmSciTech

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“…Additional intricacies of this enzyme include apparent donor-to-donor variability in activity in humans (Al-Salmy, 2001;Sahi et al, 2008) and across preclinical species and strains, where rats generally have low activity and dogs are completely devoid of activity Garattini et al, 2008). Interest in this drug-metabolizing enzyme by the pharmaceutical industry has increased recently (Pryde et al, 2010;Garattini and Terao, 2011), with the recognition that extensive AO metabolism has led to severe clinical implications, either because of toxicological outcomes (Diamond et al, 2010) or higher-than-predicted clearance in humans (Kaye et al, 1984;Rosen et al, 1999;Dittrich et al, 2002;Akabane et al, 2011;Zhang et al, 2011), yielding unacceptable pharmacokinetic properties. In most of these cases, either metabolic pathways were only evaluated in liver microsomes or predictions of human clearance were extrapolated from preclinical species that possessed significantly lower AO activity compared with humans.…”

Section: Introductionmentioning

confidence: 86%

“…) and 30% oral bioavailability (Rosen et al, 1999), had low intrinsic clearance in hepatocytes ( -benzylguanine, it is unlikely that the low intrinsic clearance of zaleplon is due to compromised AO activity in the hepatocytes. In addition, the AO-derived metabolite of zaleplon (5-oxo) was clearly observed and characterized in our analyses (Fig.…”

mentioning

confidence: 99%

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

Hutzler

Yang²,

Albaugh³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Substrates of aldehyde oxidase (AO), for which human clinical pharmacokinetics are reported, were selected and evaluated in pooled mixed-gender cryopreserved human hepatocytes in an effort to quantitatively characterize AO activity. confirmed that the predominant oxidative metabolite was generated by AO, as expected isotope patterns in mass spectra were observed after analysis by high-resolution mass spectrometry. Second, clearance values were efficiently attenuated upon coincubation with hydralazine, an inhibitor of AO. The low exposure after oral doses of BIBX1382 and carbazeran (ϳ5% F) would have been fairly well predicted using simple hepatic extraction (f h ) values derived from cryopreserved hepatocytes. In addition, the estimated hepatic clearance value for O 6 -benzylguanine was within ϳ80% of the observed total clearance in humans after intravenous administration (15 ml ⅐ min ؊1 ⅐ kg ؊1 ), indicating a reasonable level of quantitative activity from this in vitro system. However, a 3.5-fold underprediction of total clearance was observed for zaleplon, despite the 5-oxo metabolite being clearly observed. These data taken together suggest that the use of cryopreserved hepatocytes may be a practical approach for assessing AO-mediated metabolism in discovery and potentially useful for predicting hepatic clearance of AO substrates.

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“…3 Low aqueous solubility of ZAL and its significant presystemic metabolism lead to a rather low oral bioavailability of about 30 %. 6 Various formulation techniques can be applied to overcome the low aqueous solubility of drugs without affecting their optimised pharmacological action. Among different approaches for enhancing the aqueous solubility of lipophilic drugs, cyclodextrin (CD) complexation proved to be one of the most effective.…”

Section: Zaleplon (Zal) N-mentioning

confidence: 99%

Stability and Structure of Inclusion Complexes of Zaleplon with Natural and Modified Cyclodextrins

Jablan¹,

Weitner²,

Gabričević³

et al. 2011

Croat. Chem. Acta

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Abstract. The interaction between zaleplon (ZAL) and different cyclodextrins in aqueous solutions was investigated by spectrofluorimetric and phase solubility studies. Stability constants determined by both methods showed that among natural cyclodextrins, β-cyclodextrin (βCD) formed the most stabile complex but its solubilizing efficiency was limited. Among βCD derivatives, the complex stability and solubilisation efficiency decreased in order: randomly methylated-βCD (RAMEB) > sulphobutylether-βCD (SBEβCD ) > hydroxypropyl-βCD (HPβCD). The inclusion complexes of ZAL with βCD and RAMEB were further characterised by 1 H-NMR spectroscopy and the inclusion complex formation was confirmed in both cases. ROESY spectra showed two binding modes between ZAL and βCD which exist simultaneously in the solution. The first binding mode occurs by the inclusion of the phenyl ring of ZAL into the βCD central cavity via the wider rim of the cyclodextrin cone and is dominant. The second one is formed by the inclusion of pyrazolo[1,5-a]pyrimidine ring of ZAL.(doi: 10.5562/cca1800)

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Zaleplon pharmacokinetics and absolute bioavailability

Cited by 81 publications

References 5 publications

Development and Characterization of Zaleplon Solid Dispersion Systems: A Technical Note

Development and Characterization of Zaleplon Solid Dispersion Systems: A Technical Note

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

Stability and Structure of Inclusion Complexes of Zaleplon with Natural and Modified Cyclodextrins

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