Daunorubicin Cyclosporine

K Osann, P Sweet, LM Slater. (1992). Synergistic action of cyclosporin A and verapamil on vincristine and daunorubicin resistance in multidrug-resistant human leukemia cells in vitro. Cancer Chemother Pharmacol 30 152-154. 

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...

Fig. 20.13. Potential H-bonding energy, released upon interaction with the transmembrane domains of P-gp (in arbitrary energy units, EU) for progesterone (1), propranolol (2), amitriptyline (3), diltiazem (4), amiodarone (5), colchicine (7), gramicidin S (8), daunorubicin (9), vinblastine (10), cyclosporin A, in comparison with verapamil...

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... 

A second important and practical improvement is the use of a compound that blocks the efflux of the fluorescent substrate. The measurement of the ratio of fluorescent probe accumulating in the cell with and without a Pgp blocker makes the obtained data less dependent on a number of parameters that may cause variation between cells and samples. We have chosen to use the cyclosporin analog PSC 833 as Pgp inhibitor, which, at a concentration of 2 iM, completely blocks the Pgp-mediated efflux of probes such as daunorubicin or rhodamine 123 in cells with a clinically relevant Pgp content (6,11,14). In addition, we have chosen to measure the practically more convenient cellular accumulation of probe instead of cellular retention after an efflux period, although the latter is theoretically more sensitive (15). In our experience, the use of rhodamine 123 as Pgp probe, combined with PSC 833 as Pgp inhibitor, offers a sensitive and reproducible Pgp functional assay in AML. Although we prefer to use fresh cells, appropriately frozen and thawed cells can be used for this assay, as extensively discussed previously (4,14). 

Ross, D. D., Wooten, P. J., Sridhara, R Ordonez, J. V., Lee, E. J., and Schiffer, C. A. (1993). Enhancement of daunorubicin accumulation, retention, and cytotoxicity by verapamil or cyclosporin A in blast cells from patients with previously untreated acute myeloid leukemia. Blood 82,1288-1299. 

AGj pj) (hatched and cross-hatched bars) in flupenthixol (3), cyclosporin A (4), daunorubicin... 

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]. 

Noninterfering acetaminophen, acyclovir, allopurinol, amoxicillin, amphotericin B, am-picillin, aspirin, azlocillin, bendrofluazide, bumetanide, buprenorphine, carbenidllin, cefazolin, cefotaxime, cefoxitin, ceftazidime, cefuroxime, cephalexin, chlorambucil, chloramphenicol, chlordiazepoxide, chlorpheniramine, chlorpropamide, cyclophosphamide, cyclosporin, C5d arabine, daunorubicin, dextropropoxyphene, dihydrocodeine, domperidone, flucytosine, furosemide, gentamicin, griseofulvin, melphalan, methotrexate, metochlo-pramide, metronidazole, miconazole, nabilone, netilmicin, nicotinamide, nitrazepam, penicillin G, piperacillin, prednisolone, procarbeizine, prochlorperazine, riboflavin, rifampin, sulfamethoxazole, thioguanine, tobramycin, tolbutamide, trimethoprim... 

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

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