Rifampicin midazolam

Table 4 Effect of Rifampicin (600 mg/day for 10 days) on the Absorption Kinetics of Midazolam (15 mg PO) in Healthy Volunteers ...

In a study of the effects of itraconazole 200 mg/day and rifampicin 600 mg/day on the pharmacokinetics and pharmacodynamics of oral midazolam 7.5-15 mg during and 4 days after the end of the treatment, switching from... 

Itraconazole, an inhibitor of CYP3A, and rifampicin, an inducer of CYP3A, altered the pharmacokinetics and pharmacodynamics of oral midazolam in nine healthy volunteers (54). The half-life was prolonged from 2.7 to 7.6 hours by itraconazole and reduced to 1.0 hour by rifampicin. These effects were still present, although less marked, at 4 days after withdrawal of itraconazole and rifampicin. Similarly, after acute administration, the period of drowsiness was increased from 76 to 201 minutes with itraconazole and fell to 35 minutes with rifampicin the effects were again less marked 4 days after withdrawal. 

Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol 1998 54(l) 53-8. 

Rifampicin significantly induces the metabolism of zale-plon and reduces its sedative action (20), although the effect is less than the effect of rifampicin on triazolam or midazolam, probably because they are more exclusively metabolized by CYP3A4. 

Interactions. Enzyme induction of CYP 3A, e.g. by rifampicin, reduces the plasma concentration of itraconazole. Additionally, its affinity for several P450 isoforms, notably CYP 3A4, causes it to inhibit the oxidation of a number of drugs, including phenytoin, warfarin, cyclosporine, tacrolimus, midazolam, triazolam, cisapride and terfenidine (see above), increasing their intensity and/or duration of effect. 

CYP3A4 alprazolam, calcium channel blockers, cisapride, clarithromycin, cyclosporin A, erythromycin, HIV protease inhibitors, lidocaine, midazolam, simvastatin, terfenadine carbamazepine, dexamethsone, phenobarbital, phenytoin, rifampicin, St John s wort cimetidine, erythromycin, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole... 

As parecoxib is rapidly metabolised to valdecoxib, the interactions are usually considered to be due to the effects of valdecoxib. The manufacturer of parecoxib cautions the concurrent use with carbamazepine, dexamethasone and rifampicin as their effects on parecoxib have not been studied. Valdecoxib increases the levels of dextromethorphan and omeprazole. Because of these interactions, caution is advised with drugs that are metabolised by the same isoenzymes, nameiy flecainide, metoprolol, propafenone, omeprazoie, diazepam, imipramine and phenytoin. No interaction appears to occur between parecoxib and midazolam. 

The pharmacokinetics of intravenous fulvestrant were not affected by rifampicin, an inducer of the cytochrome P450 isoenzyme CYP3A4, or ketoconazole, an inhibitor of CYP3A4. In addition, intramuscular fulvestrant did not affect the pharmacokinetics of midazolam, a substrate of CYP3A4. It is therefore unlikely that fulvestrant will be affected by drug interactions involving this isoenzyme. ... 

A pharmaeokinetie study in 10 healthy subjects found that rifampicin 600 mg daily for 5 days reduced the AUC of a single 15-mg oral dose of midazolam by 96%, and reduced the half-life by almost two-thirds. The psychomotor effects of the midazolam (as measured by the digit symbol substitution test, Maddox wing test, postural sway and drowsiness) were almost totally lost. ... 

Rifampicin is a potent liver enzyme inducer, which increases the metabolism of several benzodiazepines and the non-benzodiazepine hypnotics, zaiepion, zoipidem and zopiclone, thereby decreasing their levels. The metabolism of midazolam by the cytochrome P450 isoenzyme CYP3A4 in both liver and gut is affected. The enzyme inducing effects of rifampicin seem to predominate if isoniazid (an enzyme inhibitor) is also present. Temazepam undergoes glucuronidation and is therefore unaffected by rifampicin. 

The effect of rifampicin on oral midazolam, triazolam, zaiepion, zoipidem and zopiclone is so large that they are likely to become ineffective and an alternative should be used instead. Alprazolam is also predicted to interact because CYP3A is involved with its metabolism. ... 

Especially the inhibition or induction of cytochrome P450 subtype 3A4 (CYP 3A4) is clinically relevant, because a variety of active substances and food substances (e.g. grapefruit juice) are able to affect this enzyme. Substances inhibiting CYP 3A4 include ciclosporin, dihydropyridines, verapamil, midazolam, paclitaxel, simvastatin, lovastatin, atorvastatin, cimetidine, erythromycin, troleandomycin, ketoconazole (and other azoles). Substances inducing CYP 3A4 include steroids, rifampicin, phenobarbital and St John s wort. 

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