Verapamil and cyclosporine

Lavie Y., Cao H.t., Volner A., Lucci A., Han T.Y., Geffen V., Giuhano A.E., and Cabot M.C., 1997, Agents that reverse multidmg resistance, tamoxifen, verapamil, and cyclosporin A, block gjycosphingolipid metabolism by inhibiting ceramide glycosylation in human cancer cells./. Biol. Chem. 272 1682-1687. 

Podsiadlowski, L., V. Matha and A. Vilcinskas. Detection of a P-glycoprotein related pump in Chironomus larvae and its inhibition by verapamil and cyclosporin A. Comp. Biochem. Physiol. 121B 443-450, 1998. 

Modulation of Pgp activity is considered a potential approach to reverse MDR and improve therapeutic outcomes in cancer patients. Initial clinical studies with Pgp inhibitors such as verapamil and cyclosporin showed modest success in reversing resistance in a small number of patients, but significant... 

Ogbom MR, Crocker JFS, Grimm PC. Nifedipine, verapamil and cyclosporin A pharmacokinetics in children. Pediatr Nephrol (1989) 3, 314-16. 

Not all transporters, however, show the same preferential directions. Lee and coworkers also have discovered a pump glycoprotein in the conjunctiva with preferential flux directed toward the mucosal side of the tissue. This transporter has been shown to restrict conjunctival absorption of therapeutic agents such as cyclosporin A, verapamil, and dexamethasone. In some circumstances, transient inhibition of such xe-nobiotic transporters might be an effective means of increasing the efficacy of particular classes of therapeutic agents. 

The enzyme is the principal participant in N-demethylation reactions where the substrate is a tertiary amine. The list of substrates includes erythromycin, ethylmor-phine, lidocaine, diltiazem, tamoxifen, toremifene, verapamil, cocaine, amiodarone, alfentanil and terfenadine. Carbon atoms in the allylic and benzylic positions, such as those present in quinidine, steroids and cyclosporin A, are also particularly prone to oxidation by CYP3A4, a range of substrates is illustrated in Figure 7.10. 

Calcium channel blockers are considered the drug of first choice for the treatment of posttransplant I hypertension since they increase renal blood flow. Nifedipine, isradipine and amlopidine show little interac-l tion with cyclosporine-A. Diltiazem and verapamil elevate cyclosporine-A levels. I... 

Based on the specificity and affinity, low molecular mass efflux pump inhibitors are classified into three generations (Werle 2008a). First-generation P-gp inhibitors such as verapamil or cyclosporine are compounds that are in clinical use for other indications and exhibit additional inhibitory properties. 

Inhibitors of OATP transport are typically ster-ically bulky compounds, including anions, cations, and neutral compounds (95). Various medications have been shown to interact with OATPs, including HMG CoA reductase inhibitors, cyclosporine, quinidine, rifampin, ketoconazole, verapamil, and certain protease inhibitors. Cyclosporine and rifampin have relatively high ratios of plasma concentration to Ki, suggesting the potential for clinically significant drug-drug interactions via modulation of OATP. On the other hand, plasma concentrations of pravastatin are... 

Chan C, Maurer J, Cardella C, Cattran D, Pei Y. A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients.Transplantation 1997 63 1435-1440. 

The choice of Pgp inhibitor is not without importance. When measuring fluorescence one always has to be aware of direct interactions with fluorescence of the dye not related to the Pgp function. This can be checked in Pgp-nega-tive cell lines and AML samples. In addition, effects on other transporters than Pgp may theoretically occur, which are unwanted if one intends to have a Pgp-specific method. On the other hand, if one wishes to determine the effect of a certain drug on the cellular accumulation of a probe, whether or not related to one specific transporter, this is not an unwanted side-effect. For instance, Pgp modulators such as verapamil or cyclosporin A may be less Pgp-specific in combination with certain dyes. (For an extensive discussion of this matter see ref. 4.)... 

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. 

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]. 

---