A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: In vivo evidence for the involvement of CYP3A4 in alprazolam metabolism*

Yasui, Norio; Otani, Koichi; Kaneko, Sunao; Ohkubo, Tadashi; Osanai, Takako; Sugawara, Kazunobu; Chiba, Kazuhiro; Ishizaki, Takashi

doi:10.1016/s0009-9236(96)90179-4

Cited by 84 publications

(51 citation statements)

References 29 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%

“…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), inhibits the metabolism of al-prazolam in healthy volunteers, providing in vivo evidence for the involvement of CYP3A4.…”

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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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“…[17,[27][28][29][30][31][32][33][34][35] or 77.7 ml/min for a man of 70 kg body weight. The CL R was calculated as 16.6 ml/ min as the product of CL oral and f e (21.4%) [11].…”

Section: Calculation Of CL Int In Vivo In Humansmentioning

confidence: 99%

In Vitro/in Vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans

Hirota

Iwatsubo³

et al. 2001

Biopharm & Drug Disp

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We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CL(int)) for 4-hydroxylation and CYP3A4 content and between the CL(int) for alpha-hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CL(int) for CYP3A4 was about 2-fold higher than the CL(int) for CYP3A5 in the case of 4-hydroxylation. However, the CL(int) for CYP3A5 was about 3-fold higher than the CL(int) for CYP3A4 in the case of alpha-hydroxylation. The metabolic rates for 4- and alpha-hydroxylation increased as the added amount of cytochrome b(5) increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b(5). The values of CL(int), in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CL(int) value (sum of 4- and alpha-hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitro K(i) values and reported pharmacokinetic parameters of ketoconazole was 2.30-2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73-1.79 vs 1.58-1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants.

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“…Since alprazolam is one of the most commonly prescribed agents in this class, it is important to characterize the magnitude of the in vivo e¤ect of sertindole on the metabolism of this compound, which is extensively metabolized by CYP3A4 (Greenblatt et al 1996;Yasui et al 1996). Accordingly, this study was designed to assess the potential e¤ects of sertindole on alprazolam pharmacokinetics, after 1.0 mg single doses of alprazolam administered alone and in the presence of sertindole.…”

Section: Introductionmentioning

confidence: 99%

Lack of multiple dosing effect of sertindole on the pharmacokinetics of alprazolam in healthy volunteers

et al. 1998

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The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of alprazolam was investigated. Fourteen subjects who completed the study received a single 1 mg dose of alprazolam without or with concomitant sertindole 12 mg daily. Coadministration of sertindole and alprazolam led to a half-hour decrease (P < 0.05) in mean Tmax value (alone: 1.2 h, in combination: 0.7 h) and a 1.6-h increase in the mean t1/2 value (12.5 +/- 3.2 versus 14.3 +/- 3.4 h, P < 0.05) of alprazolam. The mean Cmax (18.5 +/- 4.9 versus 18.5 +/- 4.8 ng/ml) and AUC (266 +/- 68 versus 275 +/- 57 ng x h/ml) values of alprazolam did not change statistically significantly in the presence of sertindole (P > 0.05). These pharmacokinetic changes are minor and not considered to be of clinical significance. Although both sertindole and alprazolam are substrate for CYP3A4 (cytochrome P-450 3A4), the results in this study suggest that sertindole is not an inhibitor of the metabolism of alprazolam.

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A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: In vivo evidence for the involvement of CYP3A4 in alprazolam metabolism*

Cited by 84 publications

References 29 publications

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam

In Vitro/in Vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans

Lack of multiple dosing effect of sertindole on the pharmacokinetics of alprazolam in healthy volunteers

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