Etoposide Cyclosporine

As standards digoxin, etoposide, Cyclosporin A, Colchicine (all for MDR 1), Bromosulfophthalein, Furosemide (for MRP2) and Metothrexate, topotecan (for ABCG2) can be used. Efflux ratio of the compound is compared to ratio of standards. 

Fig. 20.11. Substrate quality obtained by comparing basolateral-to-apical with apical-to-basolateral transport of substrates in polarized cell monolayers of MDR1-transfected cell lines [86] plotted versus (A) the log of the air/water partition coefficient, or (B) H-bond energy (arbitrary units, EUh cf. text). Units of the air/ water partition coefficient were [M ]. Compound (concentrations in Ref. [86] in brackets) were clozapine (50 nM) (1) cyclosporin A (2 tM) (2) daunorubicin (3) dexamethasone (2 tM) (4) digoxin (2 pM) (5) domperidone (2 pM) (6) etoposide (7) flunitrazepam (500 nM) (8) haloperidol (50 nM) (9) ivermectin (50 nM) (10) loperamide (2 pM) (11) morphine (2 pM) (12) ondansetron...

Cyclosporin A readily inhibits CYP3A metabolism and may lead to significant pharmacokinetic interactions (288). Several studies have been performed using cyclosporin A as a P-gp modulator in combination with etoposide, doxorubicin, and paclitaxel as described below. 

The effects of cyclosporin A on the pharmacokinetics of etoposide have been determined and were shown to be dose dependent. A variable range of cyclosporin A concentrations was obtained (297-5073 ng/mL), and it was observed that patients with higher cyclosporin A concentrations also had larger increases in etoposide AUC (290). Results from studies using clinically relevant plasma concentrations of cyclosporin A (1000-5000 ng/mL) as a P-gp inhibitor resulted in mean 48%, 52%, and 52% decreases in the systemic, renal, and nonrenal clearances of intravenously administered etoposide (232,290). Similar decreases in the systemic, renal, and nonrenal clearances of doxorubicin were observed with administration of cyclosporin A (232,291). 

Lum BL, Kaubisch S, Yahanda AM, et al. Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 1992 10(10) 1635-1642. 

Acyclovir Erythromycin Ivermectin Itraconazole Rifampin Actinomycin D Daunorubicin Doxorubicin Docetaxel Epirubicin Etoposide Imatinib Irinotecan Paclitaxel Vinblastine Vincristine Amprenavir Indinavir Nelfinavir Ritonavir Saquinavir Cyclosporine A Tacrolimus Digoxin Quinidine Verapamil Diltiazem Aldosterone Cortisol Corticosterone Dexamethasone Hydrocortisone Cyclosporine Metkephamid Enkephalin... 

There is a high level of expression of P-gp in the epithelial cells of the small intestine. Compounds that have been found to be substrates exhibit a wide range of chemical structures. However, they tend to be lipophilic and, for some, cationic, such as anthracyclines, vinca alkaloids, cyclosporin, etoposide, and celiprolol. It has been shown that taxol, an anti-microtubule anticancer drag, was not absorbed after oral administration in pre-clinical trials. This can probably be attributed to P-gp, since the flux from the... 

The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was "Posicor Withdrawal Reflects Complexity of Interaction Profile" (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vinblastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor s decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage. 

The solubilization techniques for injectable formulations are similar to those in oral formulations and include pH adjustment, mixed aqueous/organic cosolvents, organic solvent mixtures, cyclodextrin com-plexation, emulsions, liposomes, polymeric gels, and combinations of techniques. " Molecules that are non-ionizable, lipophilic, and non-polar are challenging to formulate owing to their low water solubility and no effect of pH on solubility. Examples include paclitaxel, docetaxel, cyclosporin A, etoposide, loraze-pam, tacrolimus, testosterone enanthate, and halo-peridol decanoate, and they are all solubilized in non-aqueous solutions composed entirely of organic solvent(s), which are usually but not always diluted prior to administration. 

Bisogno G, Cowie F, Boddy A, Thomas HD, Dick G, Pinkerton CR. High-dose cyclosporin with etoposide— toxicity and pharmacokinetic interaction in children with solid tumours. Br J Cancer 1998 77(12) 2304-9. 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, carbamazepine, carbimazole, cyclosporine, daclizumab, diuretics, etoposide, etretinate, grapefruit juice, indomethacin, isoniazid, itraconazole, ketoconazole, licorice, live vaccines, methotrexate, naproxen, oral contraceptives, pancuronium, phenobarbital, phenytoin, rifampicin, troleandomycin... 

In this context, studies on transformants of LLC-PKi cells that expressed P-gp derived from human, monkey, canine, rat, and mouse impressively showed altered efflux activities and rankings depended on the species for substances such as clarithromycin, daunorubicin, digoxin, etoposide, paclitaxel, quinidine, ritonavir, saquinavir, verapamil, and vinblastine [76]. Subsequent experiments confirmed different inhibitory effects of verapamil and quinidine on the transport of daunorubicin, digoxin, and cyclosporin A across LLC-PKi cells with P-gp from different species [77]. These reports clearly pointed out that qualitative statements, whether a substance is a transporter substrate or not, are possible. But it was also underlined that one has to be really careful when applying permeability data of in vitro experiments or in vivo animal studies to human conditions. In general, the functional consequences of species variation may vary from compound to compound, and further studies are needed on this aspect [78]. 

Acetaminophen, aldrin, alfentanil, amiodarone, aminopyrine, amitriptyline, amprenavir, androstenedione,antipyrine, astemizole, benzphetamine, budesonide, carbamazepine, celecoxib, chlorpromazine, chlorzoxazone, cisapride, clarithromycin, clozapine, cocaine, codeine, cortisol, cyclophosphamide,cyclosporin, dapsone, delavirdine, dextromethorphan, digitoxin, diltiazem, diazepam, erythromycin, 17j3-estradiol, ethinylestradiol, etoposide, felbamate, fentanyl, flutamide, hydroxyarginine, ifosphamide, imipramine, indinavir, ketoconazole, lansoprazole, loratidine, losartan, lovastatin, (iS)"mephen3d in, methadone, mianserin, miconazole, mifepristone, nelfinavir, nevirapine, nicardipine, nifedipine, odansetron, omeprazole, orphenadrine, proguanil, propafenone, quinidine, quinine, rapamycin, retinoic acid, ritonavir, saquinavir, selegiline, serindole, sufentanil, sulfinpyrazone, tacrolimus, tamoxifen, tamsulosin, taxol, teniposide, terfenadine, tetrahydrocannabinol, theophylline, toremifene, triazolam, trimethadone, trimethoprim, troleandomycin, verapamil, warfarin, zatosetron, Zolpidem, zonisamide... 

Simultaneous acetaminophen, aspirin, carmustine, chlorambucil, Qdarabine, dacarba-zine, diclofenac, etoposide, 5-fluorouracil, ifosfamide, indomethadn, lomustine, methotrexate, naproxen, salicylic acid, tegafur, teniposide, thioguanine Noninterfering betamethasone, carboplatin, cyclophosphamide, cyclosporine A, ibuprofen, thiotepa... 

Anticancer drugs etoposide, doxorubicin, vincristine Ca + channel blockers dUtiazem, verapamil HIV protease inhibitors indinavir, ritonavir Antibiotics/antifungals erythromycin, ketoconazole Hormones testosterone, progesterone Immunosuppressants cyclosporine, FK506 (tacrolimus)... 

CYP3A4/3A5/3A7 Macrolides, cyclosporine, tacrohmus, Ca + channel blockers, midazolam, terfenadine, hdocaine, dapsone, quinidine, triazolam, etoposide, teniposide, lovastatin, alfentanU, tamoxifen, steroids Efficacy of immunosuppressive effects of tacrolimus... 

CYP2C9 Cyclosporine, Ifosfamide, Etoposide Nefazodone, Losartan, Warfarin, Tamoxifen, Phenytoin... 

MRC 235 Relapsed and refractory AML Cyclosporin Daunorubicin Cytarabine Etoposide No benefit Yin et al. (2001)... 

LacayoNJ, Lum BL, BectonDL, Weinstein H, Ravindranath Y, Chang MN, BomgaarsL, Lau-er SJ, Sikic BL Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukem ia. Leukemia (2002) 16, 920-7. 

Maia RC, Noronha H, Vasconcelos FC, Rumjanek VM. Interaction of cyclosporin A and etoposide. Clinical and in vitro assessment in blast phase of chronic myeloid leukaemia. Clin Lab Haematol (1997) 19,215-7. 

Anecdotal responses have been cited with cyclosporin A (206), monoclonal antibodies targeted against T cells (207,208) humanized anti-CD4 antibodies (18), alemtuzumab (CAMPATH-IH), a monoclonal antibody directed against CD52 (81,209), 15-deoxyspergualin (210,211), and etoposide (180,212), and autologous hematopoietic stem cell transplants (213), but data are limited to a few cases in uncontrolled trials. 

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