Quinidine CYP3A4 inhibitors

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

Cardiac dysrhythmias Life-threatening cardiac dysrhythmias or sudden death have occurred in patients using cisapride, pimozide, or quinidine concomitantly with itraconazole or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated. 

Coadministration of CYP3A4 inhibitors could cause a dangerous increase in the level of digitoxin also. Thus, quinidine increases the blood level and decreases clearance of digitoxin. 

One of the complicating factors with chemical inhibitors is that a chemical that inhibits one CYP enzyme may activate another enzyme. If both enzymes contribute to metabolite formation, the inhibitory effect of the chemical on one enzyme may be offset by its activating effect on the other enzyme. a-Naphthoflavone is an inhibitor of CYP1A2 but an activator of CYP3A4, whereas quinidine is an inhibitor of CYP2D6 but, in certain cases, an activator of CYP3 A4 (184-186). a-Naphthoflavone and quinidine both appear on the list of FDA preferred and acceptable chemical inhibitors, so their ability to inhibit one enzyme but activate another are relevant to reaction phenotyping. 

C. Delavirdine Drug interactions are a major problem with delavirdine, which is metabolized by both CYP3A4 and CYP2D6. Its blood levels are decreased by antacids, ddl. phenytoin. rifampin, and nelfinavir. Conversely, the blood levels of delavirdine are increased by azole anti-fiingals and macrolide antibiotics. Delavirdine increases plasma levels of several benzodiazepines, nifedipine, protea.se inhibitors, quinidine, and warfarin. Delavirdine causes skin rash in up to 20% of patients, and the drug should be avoided in pregnancy since it is teratogenic in animals. 

Pyrimethamine/sulfadoxine and tetracycline have been shown to increase halofantrine levels, and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine, and quinidine might also increase the toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with the concurrent use of potent CYP3A4 inhibitors. Fatty food markedly increases halofantrine levels, consequently it is recommended that halofantrine is taken on an empty stomach. Grapefruit juice has a similar effect Note that halofantrine is no longer widely marketed. 

A study in animals found that ketoconazole roughly doubled the AUC of halofantrine and inhibited its metabolism to the equipotent metabolite, desbutylhalofantrine. In in vitro studies, ketoconazole markedly inhibited the metabolism of halofantrine by CYP3A4. It has been suggested that the rise in halofantrine levels could reasonably be expected to increase toxicity. Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited the metabolism of halofantrine in vitro, and might therefore do so clinically. The manufacturer recommended caution with the concurrent use of potent CYP3A4 inhibitors. Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit the metabolism of halofantrine by CYP3A4, see (b) below. 

Theoretically the metabolism of venlafaxine may be inhibited by CYP2D6 inhibitors or substrates such as diphenhydramine, melperone, quinidine or thioridazine. CYP3A4 inhibitors such as ketoconazole may also have some effect. An isolated case describes a hypertensive crisis associated with venlafaxine and di-sulfiram. The manufacturers predict that the use of triptans with venlafaxine may have additive effects on serotonin, which could lead to the serotonin syndrome. 

Note / CYP3A4 values were ealculated [Eq.(4.18)] by the decreased oral clearance (or systemic clearance) or increased AUC of the drugs in the presence of ketoconazole or other individual CYP3A4 inhibitors as indicated by numbers in parentheses (1) troleandomycin (2) ritonavir (3) mibefradil (4) fluoconazole (5) itraconazole (6) clarithromycin (7) Saquinavir (8) erythromycin (9) quinidine (10) cemetidine. 

Figure 7.5 Mucosal-to-submucosal (m-s), Tapp values across human buccal culture of midazolam (CYP3A4 substrate), bufuralol (CYP2D6 substrate), tolbutamide (CYP2C9 substrate), and the nonmetabolized, high-permeability control compound caffeine (average SEM, N = 1 — 3 replicates). (Asterisk) in the presence of CYP inhibitors (CYP3A4-ketoconazole CYP2D6-quinidine CYP2C9-suphaphenazole). In all treatments integrity of the culture was verified by permeation of Lucifer yellow (< 2.0 x 10-6 cm/s). Results from internal study by Absorption Systems Company.

However, quinidine is not biotransformed by CYP2D6, even though it binds to this enzyme with high affinity [unbound A) < 1 nM (34)]. Quinidine is actually biotransformed by CYP3A4 (35), and is a competitive inhibitor of this enzyme [A) as low as 5.4 pM (36)], although its effects are highly dependent on the CYP3A4 substrate employed. 

Aripiprazole plasma levels are increased by inhibitors, and decreased by inducers, of CYP3A4. Quinidine increases aripiprazole levels. The manufacturers advise caution with drugs that can prolong the QT intervaL Food and famotidine do not have a clinically relevant effect on the pharmacokinetics of aripiprazole, and aripiprazole does not affect the pharmacokinetics of dextromethorphan, omeprazole, and warfarin. 

Fluoxetine inhibits the activity of the cytochrome P450 isoenzyme CYP2D6 within the liver so that the metabolism of oxycodone to an aetive metabolite oxymorphone is reduced. The metabolism of hydroeodone and similar opioids may also be affected by CYP2D6 inhibitors, see Opioids Codeine and related drugs + Quinidine , p.l84. Buprenorphine and morphine are not metabolised by CYP2D6, so their metabolism would not be expeeted to be affected by fluoxetine. Buprenorphine is metabolised by CYP3A4 and so fluvoxamine might be expected to inhibit its metabolism to some extent. 

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