Phenytoin Cyclophosphamide

In three patients treated with cyclophosphamide, phenytoin co-medication increased the formation of the iS -enantiomer (but not the 7 -enantiomer) of the dechlor-oethylated cyclophosphamide metabolite (71). The findings also suggested that phenjdoin increased the clearance of both R- and. S -cyclophosphamide to 4-hydroxycyclo-phosphamide (the activation pathway). The clinical relevance of these findings is unclear. 

Allopurinol, barbiturates, carbamazepine, cephalosporins, cyclophosphamide, ethambutol, fluconazole, ibuprofen, lamotrigine, macrolides, nitrofurantoin, penicillins, phenytoin, propranolol, quinolones, sulfonamide antimicrobials, sulindac, tetracyclines, thiazides, valproic acid, and vancomycin... 

Azathioprine, chloramphenicol, colchicine, cyclophosphamide, cytarabine, 5-fluorodeoxyuridine, 5-fluorouracil, hydroxyurea, mercaptopurine, metformin, methotrexate, phenobarbital, phenytoin, primidone, proton pump inhibitors, pyrimethamine, sulfasalazine, and vinblastine... 

Incompatibilities of metoclopramide depend on drug concentration, pH, and temperature. It is incompatible with cephalosporins, chloramphenicol, sodium bicarbonate, doxorubicin, cisplatin, and cyclophosphamide. Caution should be exercised with simultaneous administration of metoclopramide with lithium, sym-pathomimetics, antidepressants, bromocriptine, and carbamazepine. Omperazole interacts with tolbutamide, clarithromycin, and phenytoin. Coadministration of rantidine and cisapride increases the plasma concentration of rantidine. Abuse of senna laxative has been reported and may cause hepatitis.176-178... 

A4 34.1 Acetaminophen, caffeine carbamazepine, codeine, cortisol, erythromycin, cyclophosphamide, (S)-and (R)-warfarin, phenytoin, testosterone, halothane, zidovudine... 

Williams ML, Wainer IW, Embree L, Barnett M, Granvil CL, Ducharme MP. Enantioselective induction of cyclophosphamide metabohsm by phenytoin. Chirality 1999 ll(7) 569-74. 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Clinically important, potentially hazardous interactions with albendazole, aminoglutethimide, aspirin, bexarotene, carbamazepine, cyclophosphamide, dasatinib, diuretics, ephedrine, imatinib, itraconazole, lapatinib, live vaccines, lopinavir, methotrexate, phenobarbital, phenytoin, praziquantel, primidone, rifampicin, rifampin, temsirolimus, warfarin... 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, aspirin, chlorambucil, cimetidine, clarithromycin, cyclophosphamide, cyclosporine, dicumarol, diuretics, docetaxel, estrogens, grapefruit juice, indomethacin, influenza vaccines, itraconazole, ketoconazole, lansoprazole, live vaccines, methotrexate, montelukast, omeprazole, oral contraceptives, pancuronium, phenobarbital, phenytoin, ranitidine, rifampicin, rifampin, timolol, tolbutamide, vitamin A... 

Proton pnmp inhibitors Omeprazole Lansoprazole Pantoprazole Antiepileptics Diazepam Phenytoin Phenobarbitone Amitriptyline Clomipramine Cyclophosphamide Progesterone... 

Amitriptyline, barbiturates, chlorproguanil, citalopram, clomipramine, clozapine, cyclophosphamide, diazepam, hexobarbital, imipramine, pentamidine, phenobarbital, phenytoin, propranolol, quinine, (S)- and (Jf)-warfarin, zidovudine... 

CYP2B6 <5 1-2 Bupropion Carbamazepi ne Cyclophosphamide Selegiline Flunitrazepam Meperidine Bupropion Selegiline Ethinylestradiol Phencyclidine Tamoxifen Ticlopidine Clotrimazole Carbamazepine Phenobarbital Phenytoin Pioglitazone Rifampin Troglitazone Valproic acid Ritonavir... 

In most cases the mechanism is not known. Stimulators of vasopressin secretion include vincristine, cyclophosphamide, tricyclic antidepressants, nicotine, epinephrine, and high doses of morphine. Lithium, which inhibits the renal effects of vasopressin, also enhances vasopressin secretion. Inhibitors of vasopressin secretion include ethanol, phenytoin, low doses of morphine, glucocorticoids, fluphenazine, haloperidol, promethazine, oxilorphan, and butorphanol. Carba-mazepine has a renal action to produce antidiuresis in patients with central diabetes insipidus but actually inhibits vasopressin secretion via a central action. 

Bioactivation to a free radical intermediate has been implicated in the teratological mechanism for a number of xenobiotics, including phenytoin and structurally-related AEDs, benzo[a]pyrene, thalidomide, methamphetamine, valproic acid, and cyclophosphamide (Fantel 1996 Wells et al. 2009 Wells and Winn 1996). Unlike in the case of most CYPs, the embryo-fetus has relatively high activities of PHSs and lipoxygenases (LPOs), which via intrinsic or associated hydroperoxidase activity can oxidize xenobiotics to free radical intermediates (Fig. 10) (Wells et al. 2009). These xenobiotic free radical intermediates can in some cases react with double bonds in cellular macromolecules to form covalent adducts, or more often react directly or indirectly with molecular oxygen to initiate the formation of potentially teratogenic reactive oxygen species (ROS). 

Phenytoin Carbamazepine Sodium valproate Doxorubicin Cisplatin Cyclophosphamide Altretamine Papillary adenocarcinoma of the ovaries Seizures occurred 2 to 3 days after starting chemotherapy. All drug levels dropped to one-third or iower. Doses increased to compensate, which led to phenytoin toxicity when the chemotherapy finished. 5... 

Phenytoin followed by Carbamazepine Vincristine Cytarabine Hydroxycarbamide Daunorubicin Methotrexate Tioguanine Cyclophosphamide Carmustine Stage iV T-ceii iymphoma Phenytoin faiied to reach therapeutic ieveis and so was substituted with carbamazepine. Chemotherapy caused carbamazepine levels to drop below therapeutic levels resulting in seizures, increasing the dose from 30 to 50 mg/kg per day prevented subtherapeutic ieveis. 8... 

Phenytoin increases the metabolism of cyclophosphamide and ifosfamide, but the clinical relevance of this is uncertain. Both unchanged and increased efficacy has been suggested. 

The alteration in the pattern of ifosfamide metabolites suggested that phenytoin had induced the activity of the cytochrome P450 isoenzyme CYP2B6, and to a lesser extent CYP3A4. The pattern of the increase in cyclophosphamide clearance is also consistent with induction of CYP2B and CYP3A. See also Cyclophosphamide or Ifosfamide + Barbiturates , p.623. 

The alteration in the metabolism of cyclophosphamide and ifosfamide caused by phenytoin is not surprising, but the clinical importance of any changes remains to be established. The authors of the study from the 1970s concluded that phenytoin was unlikely to have much effect on the antitumour and toxic effects of cyclophosphamide. Conversely, the authors of the more recent studies suggest that phenytoin may increase the therapeutic efficacy of cyclophosphamide and ifosfamide. Further study is needed. 

Note that reduced phenytoin levels and seizures have been reported in a patient receiving chemotherapy including cyclophosphamide, see Table 14.1 ,(p.519). 

---