Methadone Protease inhibitors

Drugs that may be affected by nevirapine include rifamycins, clarithromycin, oral contraceptives, efavirenz, ketoconazole, methadone, protease inhibitors, warfarin, zidovudine. 

Some P-gp inhibitors have been tested in clinical trials (e.g., GF120918, PSC 833) [88, 89], Shortly before birth, it is often desirable to expose the fetus to anti-HIV medications to prevent HIV transmission from the mother to the fetus during delivery. Preperfusion with P-gp inhibitors increased fetal penetration of the protease inhibitor saquinavir in in vitro placental models, and it has been hypothesized that P-gp may be responsible for limiting fetal exposure to HIV protease inhibitors, methadone, anthracyclines, and taxanes [90-93],... 

Deaths, cardiac and resp have been reported during initiation and conversion of pain pts to methadone Tx from Tx w/ other opioids Uses Severe pain detox w/ maint of narcotic addiction Action Narcotic analgesic Dose Adults. 2.5-10 mg IM q3-8h or 5-15 mg PO q8h titrate as needed Feds. 0.7 mg/kg/24 h PO or IM -s- q8h T slowly to avoid resp depression X in renal impair Caution [B/D (prolonged use/high doses at term), + (w/ doses =/> 20 mg/24 h)], severe liver Dz Disp Tabs, inj SE Resp depression, sedation, constipation, urinary retention, T QT interval, arrhythmias Interactions T Effects W/ cimetidine, CNS depressants, protease inhibitors EtOH T effects OF anticoagulants, antihistamines, barbiturates, glutethimide, methocarbamol ... 

Since nevirapine is metabolized by the cytochrome P-450 system and induces 3A4 and 2B6, other drugs that are also metabolized by these isoenzymes will have low plasma levels when given in combination. It also increases the clearance of methadone and results in methadone withdrawal. Nevirapine decreases the plasma concentrations of norethindrone, ethinyl estradiol and protease inhibitors (HIV). 

In an in vitro study of the effects of the HIV-1 protease inhibitors, ritonavir, indinavir, and saquinavir, which are metabolized by the liver CYP3A4, all three protease inhibitors inhibited methadone demethylation and buprenor-phine dealkylation in rank order of potency ritonavir > indinavir > saquinavir (53). Clinical studies are required to establish the further relevance of these observations. 

Moreno A, Perez-Elias MJ, Casado JL, Munoz V, Antela A, Dronda F, Navas E, Moreno S. Long-term outcomes of protease inhibitor-based therapy in antiretroviral treatment-naive HIV-infected injection drug users on methadone maintenance programmes. AIDS 2001 15(8) 1068-70. 

Iribarne C, Berthou F, Carlhant D, Dreano Y, Picart D, Lohezic F, Riche C. Inhibition of methadone and buprenor-phine N-dealkylations by three HIV-1 protease inhibitors. Drag Metab Dispos 1998 26(3) 257-60. 

METHADONE, PETHIDINE PROTEASE INHIBITORS 1 efficacy of methadone, with risk of withdrawal, when coadministered with amprenavir, nelfinavir, ritonavir (with or without lopinavir) or saquinavir Uncertain possibly due to induction of CYP3A4 and CYP2D6 Monitor closely for opioid withdrawal, and t dose of methadone as necessary. This advice includes co-administration of methadone with low-dose ritonavir. Short-term use of pethidine is unlikely to cause a problem... 

McCance-Bvatz EF, Rainey PM, Friedland G, Jatlow P (2003) The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained padents. Clin hifect Dis 37 476 82. 

Rifampin Azoles, cyclosporine, methadone propranolol, protease inhibitors (PI), oral contraceptives, tacrolimus, warfarin Increased metabolism of other agent Avoid if possible... 

Because nevirapine induces CYP3A4, this drug may lower plasma concentrations of coadministered CYP3A4 substrates. Methadone withdrawal has been reported in patients receiving nevirapine, presumably as a consequence of enhanced methadone clearance. Plasma ethinyl estradiol and norethindrone concentrations decrease by 20% with nevirapine, and alternative methods of birth control are advised. Nevirapine also can reduce concentrations of some coadministered HIV protease inhibitors. 

Not known. The findings are the opposite of those originally predicted based on in vitro data showing inhibition of methadone metabolism (principally mediated by the cytochrome P450 isoenzyme CYP3A). One study found a slight increase in methadone elimination, but this was not mediated by C YP3A. It is possible that these protease inhibitors induce the... 

Beauverie P, Taburet A-M, Dessalles M-C, Furlan V, Touzeau D. Therapeutic drug monitoring of methadone in HIV-infected patients receiving protease inhibitors. AIDS (1998) 12, 2510-11,... 

---