Erythromycin, cytochrome decrease

Sildenafil doses should be decreased when any potent cytochrome P450 3A4 inhibitor is used (e g., cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and saquinavir). Vardenafil doses vary accordingto which agent is used (2.5 mg q 72 h for ritonavir, 2.5 mg q 24 h for indinavir, ketoconazole 400 mg daily, and itraconazole 400 mg daily and 5 mg q 24 h for ketoconazole 200 mg daily, itraconazole200 mg daily, and erythromycin). Tadalafil doses are reduced only when it is used with the most potent cytochrome P450 3A4 inhibitors (e g., ketoconazole or ritonavir). 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is l-(2-pyrimidyl)-piperazine (1-PP), which has K2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2-4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 

Biotransformation of benzodiazepines occurs in the liver, where the drugs vmdergo phase I metabolism by the cytochrome P450 enzyme complex. Other drugs that may compete with benzodiazepines for liver microsomal enz)mies and result in decreased metabolism of benzodiazepines are erythromycin, ketoconazole, verapamil and... 

Erythromycin is a substrate for the cytochrome P450 (CYP 450) 3A4 isoenzyme. Once bound to CYP 3A, erythromycin stimulates its own metabolism via demethylation and oxidation to nitroalkane metabolites. These nitroalkane metabolites appear to form stable complexes with the iron of the CYP 3A4 isoenzyme, decreasing its functional capacity. Depending upon the erythromycin dose and duration of therapy, CYP 3A4 activity could be inhibited to undetectable activity and serves as the basis of erythromycin-associated metabolic-based drug-drug interactions. 

Cisapride is metabolized by a cytochrome P450 isozyme that is inhibited by erythromycin and by ketoconazole. Decreased clearance of the antihistaminic drugs astemizole and terfenadine (now withdrawn) may also result in cardiotoxicity. The answer is (E). 

Fluvoxamine decreased the mean total plasma clearance of ropivacaine by 68% from 354 to 112 mL/minute, and almost doubled the half-life of ropivacaine in a randomised, crossover study in 12 healthy subjects. Fluvoxamine was given at a dose of 25 mg twice daily for 2 days, and a single 40 mg intravenous dose of ropivacaine was given over 20 minutes one hour after the morning dose of fluvoxamine on the second day. Fluvoxamine is a potent inhibitor of the cytochrome P450 isoenzyme CYP1A2 and so reduces the metabolism of ropivacaine to its major metabolite 3-hydroxyropivacaine. In one study in healthy subjects the combination of fluvoxamine with erythromycin, an inhibitor of CYP3A4, which on its own has little effect on the pharmacokinetics of ropivacaine, was found to decrease the clearance of ropivacaine more than fluvoxamine alone. ... 

The study found lidoeaine clearance was reduced by fluvoxamine and further decreased by concurrent erythromycin. The cytochrome P450 isoenzymes CYPlA2 and CYP3A4 are involved in lidoeaine metabolism. An in vitro study found that fluvoxamine (a CYP1A2 inhibitor) was a more potent inhibitor of lidoeaine metabolism than erythromycin (a CYP3A4 inhibitor). See also Lidoeaine + Erythromycin , above and Anaesthetics, local + Fluvoxamine , p.l 10. 

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