Clearance methadone

Oda, Y., Kharasch, E. D., Metabolism of methadone and levo-a-acetyl-methadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4) potential contribution of intestinal metabolism to presystemic clearance and bioactivation, J. Pharmacol. Exp. Ther. 2001, 298, 1021-1032. 

Methadone Coadministration increased oral methadone clearance by 22%. An increased methadone dose may be required in a small number of patients. 

Efavirenz inhibits the plasma levels of indinavir, saquinavir and amprenavir and increases the concentrations of ritonavir and nelfinavir. It also lowers the plasma levels of methadone, phenytoin, carbamazepine and phenobarbital. Drugs that stimulate the cytochrome P-450 system will increase its clearance and should not be coadministered. 

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). 

Methadone is an MOR(OP3, i) receptor agonist with pharmacological properties similar to those of morphine. It is an attractive alternative MOR opioid receptor analgesic, because of its lack of neuroactive metabolites, a clearance that is independent of renal function, good oral systemic availability, a longer half-life with fewer doses needed per day, and extremely low cost. It is mainly metabolized by CYP3A4. 

There have been another 11 cases showing a direct link between QT interval prolongation and oral methadone maintenance treatment at doses of 14-360 micrograms/ day (15) (16). QT interval prolongation can lead to arrhythmias such as torsade de pointes, especially when high doses of methadone are given intravenously and associated with concomitant use of cocaine and/or medications that inhibit the hepatic clearance of methadone (e.g. antidepressants and antihistamines). 

In a randomized, double-blind, placebo-controlled trial, oral fluconazole increased the serum methadone AUC by 35% (59). Although renal clearance was not significantly affected, mean serum methadone peak and trough concentrations rose significantly, while renal clearance was not significantly altered. 

BETA-BLOCKERS OPIOIDS 1. Risk of t plasma concentrations and effects of labetalol, metoprolol and propranolol t systemic effects of timolol eye drops 2. t plasma concentrations of esmolol when morphine is added 3. t plasma concentrations of metoprolol and propranolol when dextro-propoxyphene is added 1. Methadone inhibits CYP2D6, which metabolizes these beta-blockers 2. Unknown 3. i hepatic clearance of metoprolol and propanolol 1. Monitor BP at least weekly until stable 2. Monitor BP closely 3. Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.)... 

OPIOIDS ANTIFUNGALS 1, Ketoconazole T effect of buprenorphine 2. Fluconazole and itraconazole T the effect of alfentanil 3. Fluconazole and possibly voriconazole T effect of methadone this is a recognized pharmacokinetic effect but of uncertain clinical significance 1. Ketoconazole 1 the CYP3A4-mediated metabolism of buprenorphine 2.1 clearance of alfentanil 3.1 hepatic metabolism 1. The dose of buprenorphine needs to be 1 (by up to 50%) 2. i dose of alfentanil 3. Watch for T effects of methadone... 

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. 

If the nature of the time dependency is well understood and sampling is sufficient to identify model parameters, which define such expressions, a modification to the typical structural model can be explored. Specifically, as in the case of enzyme induction, changes in clearance may be expected to occur over typical time windows. By allowing the initial value of clearance, C1(0), to increase in a monoexponential manner until an asymptotic value, Cl(ss), is reached, the clearance at any time, t, can be expressed as a function of these boundary conditions and an induction rate constant, k,. Such a function (shown below) was proposed by Levy et al. and utilized by Rostami-Hodjegan et al. with certain assumptions to model methadone pharmacokinetics in opiate users. 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Grapefruit juice has been associated with a modest increase in oral methadone bioavailability. Grapefruit juice does not appear to affect the bioavailability of intravenous alfentanil or transmu-cosal fentanyl to a clinically significant extent the clearance of oral alfentanil may be reduced. 

A randomised, crossover study in 12 healthy subjects found that troleandomycin did not significantly affect oral or intravenous methadone bioavailability. Troleandomycin caused only a small reduction in methadone A-demethylation after oral methadone, suggesting only a small role for CYP3A4 in human methadone metabolism. However, one manufacturer of methadone warns that its clearance may be decreased if it is given with drugs that inhibit CYP3A4 activity, such as some maerolide antibacterials. ... 

Zidovudine effects increased. In one study the mean AUC of zidovudine was increased by 43% by methadone, and in 4 of 9 patients it was doubled. In another study, 8 HIV-positive patients starting methadone found a 29% increase in the AUC of oral zidovudine and a 41% increase in the AUC of intravenous zidovudine. Three of the 8 patients stopped zidovudine because of adverse effects or haematologic toxicity." Decreased zidovudine clearance in patients taking methadone is described in another report. ... 

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