Terfenadine Grapefruit juice

TERFENADINE GRAPEFRUIT JUICE Possibly T efficacy and T adverse effects, e.g. torsade de points Altered metabolism so parent drug accumulates Avoid concomitant intake... 

CYP3A4 is highly inducible by a large variety of commonly prescribed and utilized synthetic drugs (e.g., carbamazepine) and plant products (e.g., St. John s wort) (Roby, Anderson et al, 2000), and at the same time also is potently inhibited by various other medications (e.g., terfenadine and ketoconazole) (Jurima-Romet, Crawford etal, 1994) as well as common foodstuffs (e.g., grapefruit juice) (Oesterheld 8c Kallepalli, 1997). Since individual and ethnic/cultural groups vary dramatically in their exposure to these inducers and inhibitors, it stands to reason that... 

M. O., Tran, L. T., Spence, J. D., Bailey, D. G., Grapefruit juice terfenadine single dose interaction magnitude, mechanism and relevance, Clin. Pharmacol. Ther. 1997, 61, 401-409. 

Some chemical exposures may be hepatic enzyme inducers/inhibitors, altering the effects of drugs like warfarin. Some foods such as mono-amines, will cause reactions in patients given MAOIs grapefruit juice may interact with terfenadine and some other drugs. New diseases may cause problems heart failure causing reduced liver blood flow can reduce the metabolism of drugs like warfarin. 

CYP3A4 Amiodarone, terfenadine Carbamazepine, phenytoin Erythromycin, grapefruit juice,... 

Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996 59(4) 383-388. 

Honig PK, Wortham DC, Lazarev A, Cantilena LR. Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine. J Clin Pharmacol 1996 36(4) 345-351. 

Clifford CP, Adams DA, Murray S, et al. The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice. Eur J Clin Pharmacol 1997 52(4) 311-315. 

Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, loratadine, terfenadine, isoniazid, niacinamide, nicotinamide, propoxyphene, azoles (e.g., ketaconazole, itraconazole, and fluconazole), acetazolamide, verapamil, grapefruit juice, ... 

Figure 5.3d The metabolism of the drug terfenadine. The double lines indicate the inhibition of metabolism by other drugs such as ketoconazole or the natural product found in grapefruit juice. This leads to a rise in the blood level of the drug and toxicity.

GRAPEFRUIT JUICE TERFENADINE Statistically t Q-T interval prolongation, hence the risk of cardiac toxicity, t in AUC, maximum concentration and T max. Two-fold t half-life. Possibly t efficacy and t adverse effects, e.g. torsade de pointes Altered metabolism so the parent drug accumulates. Due to effects of grapefruit juice on CYP isoenzymes and P-gp Avoid concomitant intake. Suitable alternatives that are less harmful are available, e.g. loratidine (which is also metabolized by CYP2D6), cetrizine, desloratidine. This is despite a report that no significant cardiotoxicity is likely in normal subjects... 

Many drugs will cause adverse effects if the dose is excessive but some cause adverse effects at the correct dose in certain individuals. This can be due to an increased sensitivity of the patient because of genetic or other factors (see pp. 29-31). There may also be side effects which are not apparent at low or therapeutic doses but which become more important at higher doses. Occasionally, unexpected and serious adverse effects occur in a few patients. Sometimes this is due to an interaction between two drugs or between a drug and a food constituent such as occurred with the drug terfenadine (used to treat hay fever) and grapefruit juice (see case note, pp. 33-4). 

S. E. Rau fit al, Grapefruit juice-terfenadine single dose interaaion magnitude, mechanism, and relevance , Clinical Pharmacology and Therapeutics, 61 (1997), 401-9-... 

Adverse effects. Terfenadine can prolong the QTc interval on the surface ECG. This is especially likely to occur when the recommended dose is exceeded or the drug is administered with substances that block hepatic metabolism. Since this is dependent solely on the 3A4 isoform of cytochrome P450, offending drugs include erythromycin, ketoconazole and even grapefruit juice. Fexofenadine is the active metabolite of terfenadine and appears safe in this respect. 

Terfenadine Increases systemic availability, with cardiotoxicity at higher doses of grapefruit juice concentration (22)... 

Terfenadine can cause prolongation of the QT interval in overdose or during interactions with drugs that inhibit its metaboUsm, such as erythromycin (1), ketoconazole (2), and grapefruit juice (3). Torsade de pointes can result (4). 

Grapefruit juice substantiaUy increased the AUC and Cmax of terfenadine (3). 

Clinically important, potentially hazardous interactions with amiodarone, azithromycin, bepredil, bosentan, bretylium, cisapride, clarithromycin, disopyramide, erythromycin, erythromycin fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nefazodone, nilotinib, paroxetine, pimozide, probucol, procainamide, quinidine, quinine, ritonavir, saquinavir, sertraline, sotalol, SSRIs, terfenadine, troleandomycin, voriconazole, zileuton, ziprasidone... 

Clinically important, potentially hazardous interactions with alfuzosin, alprazolam, amphotericin B, anisindione, antacids, aprepitant, astemizole, atorvastatin, bosentan, ciclesonide, cimetidine, clorazepate, conivaptan, cyproterone, dasatinib, dexamethasone, dicumarol, didanosine, eplerenone, erythromycin, ethotoin, fentanyl, fesoterodine, fosamprenavir, fosphenytoin, grapefruit juice, HMG-CoA reductase inhibitors, imatinib, ixabepilone, lapatinib, lopinavir, lovastatin, mephenytoin, methylprednisolone, micafungin, midazolam, nilotinib, pimozide, prednisolone, prednisone, quinidine, rifampin, rimonabant, rivaroxaban, sildenafil, silodosin, simvastatin, sirolimus, solifenacin, temsirolimus, terfenadine, tolvaptan, triazolam, vardenafil, vinblastine, vincristine, warfarin... 

Clinically important, potentially hazardous interactions with amiodarone, astemizole, bepridil, carbamazepine, chloroquine, cisapride, clarithromycin, dihydroergotamine, disopyramide, ergotamine, grapefruit juice, halofantrine, haloperidol, itraconazole, ketoconazole, methadone, moxifloxacin, phenobarbital, phenytoin, pimozide, procainamide, quinidine, rifampicin, ritonavir, sotalol, St John s wort, telithromycin, terfenadine, voriconazole... 

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