Cisapride metabolism

Selective serotonin reuptake inhibitors (SSRIs) [NP] Fluvoxamine inhibits CYP3A4 and probably decreases cisapride metabolism possible ventricular arrhythmia. 

Treluyer J-M, Rey E, Sonnier M, Pons G, Cresteil T. Evidence of impaired cisapride metabolism in neonates. Br J Clin Pharmacol 2001 52 419-25. 

Drugs that affect transit time would be expected to alter the normal flora and metabolic activity of the colonic lumen. Oufir et al. (45) investigated the effects of treatment with cisapride and loperamide on fecal flora and SCFA production. By doubling the transit time with loperamide, the concentration of SCFAs was markedly increased whereas by reducing the transit time with cisapride, pH was elevated and the concentration of SCFAs was significantly reduced. 

Other orthopramides have been shown to be resistant to in vivo hydrolysis. Thus, the gastrokinetic drug cisapride (4.80) was not hydrolyzed after oral administration to dogs and humans [51]. Similarly, sulpiride (4.81), an antidepressant and antipsychotic drug, did not undergo hydrolysis in humans and laboratory animals. These compounds are metabolized by other routes, and hydrolysis of the amide bond, when it occurs at all, is only a minor pathway. 

Antihistamines, nonsedating/Cisapride/Pimozide- Cisapride and pimozide are metabolized by the cytochrome P-450 3A4 isozyme inhibitors of 3A4 can block the metabolism of these drugs, resulting in increased plasma concentrations of parent drug, which is associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, because of ventricular tachycardia of the torsades de pointes type. In vitro, nefazodone inhibits 3A4. It is recommended that nefazodone not be used in combination with cisapride or pimozide. 

Potential interaction with drugs that inhibit or are metabolized by cytochrome P-450 (3A4 and 2D6) isozymes Caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by the 3A4 isozyme (in particular, cisapride or pimozide). 

Cytochrome P450 inhibition Coadministration of delavirdine tablets with certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, calcium channel blockers, ergot alkaloid preparations, amphetamines, and cisapride may result in potentially serious or life-threatening adverse events caused by possible effects of delavirdine on the hepatic metabolism of certain drugs metabolized by CYP3A and... 

Do not administer concurrently with cisapride, midazolam, triazolam, or ergot derivatives. Competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, respiratory depression see Drug Interactions). 

CYP3A4 is involved in the metabolism of 80%-90% of all currently available drugs (Table 2). Its presence accounts for the majority of the cytochrome enzymes in the liver. It has attracted attention from both physicians and pharmaceutical companies, as there have been incidences of fatal drug interactions, which have resulted in the withdrawal of these drugs from the market (terfena-dine in 1997, astemizole in 1999, and cisapride in 2000). Combinations ofpotent CYP3A4 inhibitors and substrates can drive drug levels to the toxic range. The... 

Itraconazole contraindicated in patients with evidence of ventricular dysfunction (CHF) or a history of CHF Itraconazole is also a potent inhibitor of cytochrome P450 3A4 isoenzyme, which may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events have occurred in patients taking cisapride, pimozide, levomethadyl, or quinidine concomitantly with itraconazole. 

Cisapride [NP] Decreased metabolism of cisapride possible ventricular arrhythmias. 

Susceptible to inhibition of metabolism by CYP3A4 inhibitors. High cisapride serum concentrations can result in ventricular arrhythmias. 

Nefazodone [NP] Possibly decreased metabolism of cisapride by CYP3A4 possible ventricular arrhythmia. 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

Other nonpsychotropic drugs are also substrates (Fig. 6—17) or inhibitors of 3A4 (Fig. 6—18). It is important to understand the consequences of concomitant administration of psychotropic drugs that are either substrates or inhibitors of 3A4 with nonpsychotropic drugs that are also either substrates or inhibitors of 3A4. Notably, some 3A4 substrates such as cisapride, terfenidine, and astemazole must be metabolized, or else toxic levels of the drug can accumulate, with cardiovascular consequences such as prolonged QT interval and sudden death. Thus, they cannot be... 

Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours in some patients. Quinupristin and dalfopristin are not metabolized by cytochrome P450 enzymes but significantly inhibit CYP 3 A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleo- side reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary. 

Due to prokinetic effects in the colon, abdominal cramps and diarrhea occur in up to 15% of patients taking cisapride however significant problems are unusual. In addition, cisapride is metabolized by the hepatic cytochrome P450 CYP3 A4 enzyme. When coadministered with drugs that inhibit this enzyme (such as ketoconazole, fluconazole, macrolide antibiotics, and HIV protease inhibitors), significant increases in serum levels of cisapride may occur that rarely lead to QT prolongation on the ECG and serious cardiac arrhythmias. For this reason, cisapride was removed... 

---