Tacrolimus CYP3A4/5/7 substrate

Posaconazole is the newest triazole to be licensed in the USA. It is available only in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or three doses. Absorption is improved when taken with meals high in fat. Posaconazole is rapidly distributed to the tissues, resulting in high tissue levels but relatively low blood levels. Visual changes have not been reported, but drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented. 

In rats orally administered 1.5 mg/kg of tacrolimus (a substrate of CYP3A4) with or without 2 g/kg of a decoction of the unripe fruits or an article described as the ripe peel of bitter orange, a 72% decrease in the maximum plasma concentration of tacrolimus was observed in rats administered the decoction of the unripe fruits of bitter orange. No change in tacrolimus levels was observed in the rats administered a decoction of the ripe peels. A related in vitro study with the same plant materials indicated that the unripe fruit... 

Cyclosporine and tacrolimus are substrates of the drug-metabolizing isoenzyme CYP3A4. Multiple case reports have demonstrated that St. John s wort decreases blood levels of cyclosporine (Ahmed et al. 2001 Alscher and Klotz 2003 Barone et al. 2000 Beer and Ostermann 2001 Breidenbach et al. 2000a, 2000b Karliova et al. 2000 Mai et al. 2000 Mandelbaum et al. 2000 Moschella and Jaber 2001 Ruschitzka et al. 2000 Turton-Weeks et al. 2001). St. John s wort consumption for as little as 3 days was correlated with decreased cyclosporine blood levels (Mandelbaum et al. 2000). 

Substrates of the CYP3A4 isozyme will compete with cyclosporine, tacrolimus, and sirolimus for metabolism therefore, concentrations of both medications may be increased (usually by less than or equal to 20%). bnducers of the CYP3A4 isozyme will enhance the metabolism of cyclosporine, tacrolimus, and sirolimus therefore, concentrations of these medications may be decreased. 

An interaction of nelfinavir with the macrolide immunosuppressant tacrolimus has been reported in a patient co-infected with HIV and hepatitis C virus who had undergone orthotopic liver transplantation (18). The dose of tacrolimus had to be reduced to a 70th of the normal dose to avoid adverse effects. Nelfinavir serum concentrations were not affected by tacrolimus. The authors suggested that this effect had resulted from inhibition of the metabolism of tacrolimus, because both compounds are substrates of CYP3A4. 

There are numerous case reports where patients on a calcineurin inhibitor, such as cyclosporine or tacrolimus, began taking St. John s wort and developed significant reductions in plasma concentrations of the drugs (74-81). Both cyclosporine and tacrolimus are metabolized by the CYP3A4 enzyme system, and cyclosporine is also a substrate of Pgp (74,81). There are reports of acute graft rejections caused by low cyclosporine or tacrolimus serum concentrations in heart, liver, and kidney transplant recipients who were taking St. John s wort (75,76). 

Metronidazole is a weak inhihitor of cytochrome P450 isoenzyme CYP3A4 and it has also been suggested that metronidazole is also an inhibitor or substrate for P-glycoprotein. As tacrolimus is a metabolised by CYP3A4 and is also a substrate for P-glycoprotein, one or both of these mechanisms may he involved in this interaction. 

Drug-drug interactious Amiodarone Both amiodarone and tacrolimus are metabolized by CYP3A. Amiodarone is a potent inhibitor of CYP3A4 and can increase serum concentrations of drugs that are substrates of this enzyme. In a kidney transplant patient, the initial dose tacrolimus was empirically reduced because of an anticipated interaction with amiodarone, and because amiodarone and tacrolimus have both been implicated in prolonging the QT interval [154 ]. Even so, there was sudden and marked prolongation of the QT interval shortly after the start of treatment with tacrolimus. 

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