Inhibitors of alprazolam metabolism in vitro: effect of serotonin‐ reuptake‐inhibitor antidepressants, ketoconazole and quinidine.

Moltke, Lisa L. von; Greenblatt, David J.; Cotreau-Bibbo, M. M.; Harmatz, Jerold S.; Shader, Richard I.

doi:10.1111/j.1365-2125.1994.tb04317.x

Cited by 157 publications

(86 citation statements)

References 43 publications

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“…Therefore, the present study clearly indicates the involvement of CYP3A4 in the metabolism of alprazolam, supporting the results of previous in vitro (von Moltke et al 1994) and in vivo (Yasui et al 1996) studies. Backman et al (1996) have compared the single oral dose pharmacokinetics of midazolam, which is a probe drug for the CYP3A4 activity (Watkins 1994), between epileptic patients taking carbamazepine or phenytoin and healthy volunteers.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have suggested that neither cytochrome P450 (CYP) 2D6 (Bertilsson et al 1988) nor CYP2C19 (Otani et al 1997a) is involved in the metabolism of alprazolam. Meanwhile, the in vitro study by von Moltke et al (1994) has shown that ketoconazole, an inhibitor of CYP3A4 (Olkkola et al 1994;Watkins 1994), inhibits the 4-and ␣ -hydroxylation of alprazolam, suggesting that alprazolam is metabolized by CYP3A4. Furthermore, Yasui et al (1996) have reported that erythromycin, an inhibitor of CYP3A4 (Olkkola et al 1993;Watkins 1994) Carbamazepine has been used increasingly in the treatment of psychiatric disorders (Siris 1993;Post et al 1994;Otani et al 1996a).…”

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confidence: 99%

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Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Furukori

Otani

Yasui

et al. 1998

Neuropsychopharmacology

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The triazolobenzodiazepine alprazolam is used extensively in the treatment of anxiety and panic disorders (Greenblatt and Wright 1993). A significant concentration-effect relationship for alprazolam has been suggested in the treatment of panic disorder; optimal reduction of anxiety occurs in the plasma concentration range of 20-40 ng/ml, whereas the central nervous system (CNS) depressant side effects increase progressively at higher plasma concentrations (Greenblatt and Wright 1993).Alprazolam is metabolized primarily by the hepatic microsomal oxidation, yielding 4-and ␣ -hydroxyalprazolam as its principal metabolites (Greenblatt and Wright 1993). Previous studies have suggested that neither cytochrome P450 (CYP) 2D6 (Bertilsson et al. 1988) nor CYP2C19 (Otani et al. 1997a) is involved in the metabolism of alprazolam. Meanwhile, the in vitro study by von Moltke et al. (1994) has shown that ketoconazole, an inhibitor of CYP3A4 (Olkkola et al. 1994;Watkins 1994), inhibits the 4-and ␣ -hydroxylation of alprazolam, suggesting that alprazolam is metabolized by CYP3A4. Furthermore, Yasui et al. (1996) have reported that erythromycin, an inhibitor of CYP3A4 (Olkkola et al. 1993;Watkins 1994) Carbamazepine has been used increasingly in the treatment of psychiatric disorders (Siris 1993;Post et al. 1994;Otani et al. 1996a). However, it has been suggested that carbamazepine induces the metabolism of several psychotropic drugs (Arana et al. 1986;Backman et al. 1996;Otani et al. 1996b;1997b) by a not fully characterized enzyme induction. Previous studies have suggested that carbamazepine induces CYP3A4 (Wietholtz et al. 1989;Pirmohamed et al. 1994;Yue et al. 1994), but not CYP1A2 (Wietholtz et al. 1989), CYP2D6 (Yue et al. 1994) nor UDP-glucuronosyltransferases (Yue et al. 1994). Therefore, carbamazepine may decrease plasma concentration of alprazolam by inducing its metabolism. In fact, Arana et al. (1988) has reported that carbamazepine decreased plasma concentration of alprazolam in one psychiatric patient. However, there has been no systematic study on the effect of carbamazepine on the plasma concentration and/or metabolism of alprazolam.Therefore, we studied the effect of carbamazepine on the single oral dose pharmacokinetics of alprazolam in healthy volunteers. We also expected that the present study would provide further evidence for the involvement of CYP3A4 in the metabolism of alprazolam. METHODS SubjectsThe subjects were seven healthy male volunteers. The mean Ϯ SD of age was 32.7 Ϯ 6.6 years, and that of body weight was 60.9 Ϯ 4.6 kg. Three subjects were smokers ( Ն 10 cigarettes/day), and the remaining four were nonsmokers. The study protocol was approved by the Ethics Committee of Hirosaki University Hospital, and each subject gave his written informed consent before the study. ProtocolThe study was conducted in a double-blind, randomized crossover manner, with at least a 6-week washout period. The subjects were allocated randomly to one of the two treatment sequences, placebo-carbamazepine or carbamazepin...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Furukori

Otani

Yasui

et al. 1998

Neuropsychopharmacology

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“…It is also the case that both endogenous cortisol and alprazolam are substrates for cytochrome P450-3A4 (CYP3A4), which is responsible for metabolism to 6b-hydroxycortisol and 4-and a-hydroxyalprazolam (Ged et al, 1989;von Moltke et al, 1994). There is evidence that CYP3A4 can accommodate more than one substance and that interactions with a particular substrate can impact on the metabolism of the other (Wang et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

Pomara

Willoughby

Ritchie

et al. 2003

Neuropsychopharmacol

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Benzodiazepines (BZPs) have been shown to reduce hypothalamic-pituitary-adrenal (HPA) axis activity acutely in normal humans. In contrast, the effects of chronic BZP treatment on the HPA axis have not been well studied, especially in the geriatric population. This study examined the acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol in 68 subjects (60-83 years) who received 0.25 or 0.50 mg b.i.d. alprazolam, or 0.50 or 1.0 mg b.i.d. lorazepam, or placebo orally according to a randomized, doubleblind, placebo-controlled parallel design. Memory assessment and blood samples for plasma cortisol were obtained prior to the morning dose on days 0, 7, 14, and 21, and at 1, 2.5, and 5 h postdrug on days 0 and 21. Assessments of anxiety and depression were carried out at days 0, 7, 14, and 21 before drug administration. Plasma cortisol was affected compared to placebo only by the 0.5 mg alprazolam dose. During the first and the last day of treatment, there was a significant drop in cortisol at 2.5 h after alprazolam compared to placebo. The predose cortisol levels increased significantly during chronic alprazolam treatment, and correlations were found between these cortisol changes and changes in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose HPA axis activation in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment.

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“…Incubations were performed with diazepam alone (no inhibitor), and with coaddition with fixed concentrations of the following established CYP3A inhibitors: ketoconazole, 0.05 M; itraconazole, 1.0 M; OH-itraconazole, 0.25 M; fluconazole, 10 M; ritonavir, 0.05 M; norfluoxetine, 25 M; and fluvoxamine, 50 M (von Moltke et al, 1994bMoltke et al, , 1995Moltke et al, , 1996aMoltke et al, ,b, 1998aVenkatakrishnan et al, 2000b).…”

Section: Methodsmentioning

confidence: 99%

Microsomal Protein Concentration Modifies the Apparent Inhibitory Potency of CYP3A Inhibitors

Tran¹,

Moltke²,

Venkatakrishnan³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The effect of microsomal protein concentration on the inhibitory potency of a series of CYP3A inhibitors was assessed in vitro using Microsomal binding of drug substrates and/or metabolic inhibitors is increasingly recognized as a potential source of artifact arising in the course of in vitro studies of drug metabolism. Nonspecific binding of substrate to microsomal protein can influence availability of the substrate to the metabolizing enzyme or enzymes in vitro, and thereby yield biased estimates of enzyme kinetic parameters. These, in turn, may produce inaccurate predictions when in vitro data are used to estimate in vivo pharmacokinetics (Obach, 1996(Obach, , 1997Obach et al., 1997;McLure et al., 2000;Venkatakrishnan et al., 2000c Venkatakrishnan et al., , 2001Kalvass et al., 2001). Inhibitor binding to microsomal systems may likewise influence estimation of potency of metabolic inhibitors (Gibbs et al., 1999a). The influence of binding has been termed "inhibitor depletion" when the inhibitor interacts with the active site (Gibbs et al., 1999a). However, inhibitor depletion could also refer to nonspecific inhibitor binding to microsomal preparations, as well as to actual microsomal consumption of the inhibitor itself through biotransformation.The present study evaluated the influence of microsomal protein concentration on the inhibitory capacity of known CYP3A inhibitors. In vitro 3-hydroxylation of diazepam to temazepam was used as an index reaction to profile CYP3A activity. Two selective serotonin reuptake inhibitors (fluvoxamine and norfluoxetine), three antifungal azole agents (itraconazole, ketoconazole, and fluconazole), a metabolite of itraconazole (OH-itraconazole), and the human immunodeficiency virus protease inhibitor ritonavir were used as representative CYP3A inhibitors. These agents have different intrinsic inhibitory capacities and different binding affinities. Materials and MethodsIncubation Procedures and Index Reaction Characteristics. Liver samples from individual human donors with no known liver disease were provided by the International Institute for the Advancement of Medicine (Exton, PA), the Liver Tissue Procurement and Distribution System (University of Minnesota, Minneapolis, MN), or the National Disease Research Interchange (Philadelphia, PA). All samples were of the CYP2D6 and CYP2C19 normal metabolizer phenotype based on prior in vitro phenotyping studies. Microsomes were prepared by ultracentrifugation; microsomal pellets were suspended in 0.1 M potassium phosphate buffer containing 20% glycerol and stored at Ϫ80°C until use. Chemical reagents and drug entities were purchased from commercial sources or kindly provided by their pharmaceutical manufacturers (von Moltke et al., 1993(von Moltke et al., , 1994a(von Moltke et al., ,b, 1996aVenkatakrishnan et al., 2000a Venkatakrishnan et al., ,b,c, 2001a.Diazepam 3-hydroxylation to form temazepam was used as the index reaction for CYP3A activity (Andersson et al., 1994;Ono et al., 1996;Jung et al., 1997; Venkatakrishnan ...

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Inhibitors of alprazolam metabolism in vitro: effect of serotonin‐ reuptake‐inhibitor antidepressants, ketoconazole and quinidine.

Abstract: in vitro metabolism serotonin-specific reuptake inhibitors sertraline desmethylsertraline ketoconazole quinidine

Cited by 157 publications

References 43 publications

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

Microsomal Protein Concentration Modifies the Apparent Inhibitory Potency of CYP3A Inhibitors

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