Diltiazem enhances the effects of triazolam by inhibiting its metabolism*

Varhe, Anu; Olkkola, Klaus T.; Neuvonen, Pertti J.

doi:10.1016/s0009-9236(96)90103-4

Cited by 66 publications

(24 citation statements)

References 16 publications

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“…Both verapamil and diltiazem have been shown to considerably increase the plasma concentrations of CYP3A4 substrates such as midazolam , triazolam (Varhe et al 1996;Kosuge et al 1997), buspirone (Lamberg et al 1998) andcyclosporine (Schlanz et al 1991). In vivo, the effects of diltiazem have been of the same magnitude as those of verapamil, or even stronger.…”

Section: Discussionmentioning

confidence: 99%

Midazolam α‐Hydroxylation by Human Liver Microsomes in vitro: Inhibition by Calcium Channel Blockers, Itraconazole and Ketoconazole

Wang

Xia

Backman

et al. 1999

Pharmacology & Toxicology

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Abstract:The inhibitory effects of five calcium channel blockers (diltiazem, isradipine, mibefradil, nifedipine and verapamil) and three azole antifungal agents (itraconazole, hydroxyitraconazole and ketoconazole) on the a-hydroxylation of midazolam, a probe drug for CYP3A4-mediated interactions in humans, were studied in vifro using human liver microsomes. ICso and K, values were determined for each inhibitor. The kinetics of the formation of a-hydroxymidazolam were best described by simple Michaelis-Menten kinetics. The estimated values of V, , , and K, were 696 pmol min.-' mg-' and 7.46 pmol I-', respectively. All the compounds studied inhibited midazolam a-hydroxylation activity in a concentration-dependent manner, but there were marked differences in their relative inhibitory potency. Ketoconazole was the most potent inhibitor of midazolam a-hydroxylation (ICso 0.12 pmol I-'), being 10 times more potent than itraconazole (1Cs0 1.2 pmol I-'). The inhibitory effect of hydroxyitraconazole (ICso 2.3 pmol I-') was almost as large as that of itraconazole. Among the calcium channel blockers, mibefradil was the most potent inhibitor of the a-hydroxylation of midazolam, with an ICs0 value (1.6 pmol 1-l) similar to that of itraconazole. The other calcium channel blockers were much weaker inhibitors than mibefradil: verapamil exhibited a modest inhibitory effect with an ICso of 23 p o l I-', while isradipine, nifedipine and diltiazem, with IC50 values ranging from 57 to >lo0 pmol I-', were weak inhibitors. This rank order of potency against the a-hydroxylation of midazolam was verified by the K, values. With the exception of diltiazem, these in vitro results conform with the observed interaction potential of these agents with midazolam and many other CYP3A4 substrates in vivo in man.

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Section: Discussionmentioning

confidence: 99%

Midazolam α‐Hydroxylation by Human Liver Microsomes in vitro: Inhibition by Calcium Channel Blockers, Itraconazole and Ketoconazole

Wang

Xia

Backman

et al. 1999

Pharmacology & Toxicology

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“…However, a possible interaction between ßunitrazepam or triazolam and methadone has not been previously described. Flunitrazepam and triazolam seem to be metabolized through cytochrome P-450 (CYP) 3A4, and they are not inhibitors or inducers of drug metabolism (Luurila et al 1996;Schmider et al 1996;Varbe et al 1996).Methadone seems to be metabolized by means of CYP1A2, CYP2D6 and CYP3A4 (Eap et al 1996(Eap et al , 1997Iribarne et al 1996), and it is known that could act as an inhibitor of CYP2D6 (Wu et al 1993). Experimental data seem to conÞrm that diazepam, which is metabolized by CYP3A4 and CYP2C19 (Schmider et al 1996), did not interact at pharmacokinetic level with methadone (Pond et al 1982;Preston et al 1986).…”

Section: Discussionmentioning

confidence: 99%

Abuse liability of flunitrazepam among methadone-maintained patients

et al. 1998

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Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4mg caused euphoria-related effects as measured by increases in ARCI-MBG and "high" scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential.

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“…This is especially the case when inhibition of metabolism occurs, since this often results in increased sedative effects. Thus, azole antifungal agents, some but not all macrolides, selective serotonin reuptake inhibitors, and calcium-channel antagonists such as verapamil and diltiazem have been shown to markedly enhance plasma levels of midazolam (131,139,144,161,200,(226)(227)(228)(229)(230)(231), triazolam (132,(265)(266)(267)(268), and alprazolam (268)(269)(270)(271)(272). Moreover, central nervous effects were increased and their duration prolonged.…”

Section: Benzodiazepinesmentioning

confidence: 99%

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

Thummel

Wilkinson

1998

Annu. Rev. Pharmacol. Toxicol.

762

515

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Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.

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Diltiazem enhances the effects of triazolam by inhibiting its metabolism*

Cited by 66 publications

References 16 publications

Midazolam α‐Hydroxylation by Human Liver Microsomes in vitro: Inhibition by Calcium Channel Blockers, Itraconazole and Ketoconazole

Midazolam α‐Hydroxylation by Human Liver Microsomes in vitro: Inhibition by Calcium Channel Blockers, Itraconazole and Ketoconazole

Abuse liability of flunitrazepam among methadone-maintained patients

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

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