A phase I trial of doxorubicin (DOX) and PSC 833, a modulator of multidrug resistance (MDR)

Inhibitory Effects of a Cyclosporin Derivative, SDZ PSC 833, on Transport of Doxorubicin and Vinblastine via Human P‐Glycoprotein

“…The more effective inhibition of [ 14 C]doxorubicin transport by PSC833 suggests that combination therapy with PSC833 and doxorubicin may be clinically advantageous. In clinical trials, combination therapy with PSC833 and doxorubicin produced an increase in the area under the concentration-time curve (AUC) of doxorubicin by 20-199% 3,9,10,12) and the MDR modulator effect of PSC833 has thus been confirmed.…”

“…to circumvent MDR are currently under way. 3,[8][9][10][11][12][13] Previous in vitro studies have evaluated the efficacy of PSC833 for the reversal of MDR using the cell growth inhibition assay. 4,5,[14][15][16][17][18][19][20] They also measured uptake, efflux and accumulation of drugs to evaluate the transport activity.…”

Can multidrug resistance mechanisms be modified?

“…These phase I studies, as well as subsequent phase II studies, also led to the important observation that inhibitors such as CsA or PSC‐833 can significantly alter the pharmacokinetic clearance of chemotherapeutic agents such as etoposide, vinca alkaloids and anthracyclines ( Yahanda et al , 1992 ; List et al , 1993 ; Erlichman et al , 1994 ). Thus, in order to achieve pharmacological exposures similar to that observed with standard dosing of chemotherapeutic drugs, dosing would have to be reduced by 40–60% ( Yahanda et al , 1992 ; List et al , 1993 ; Erlichman et al , 1994 ). The altered pharmacological parameters are believed to be due to the inhibition of drug transporters functioning in the biliary system and kidneys, as well as effects on the P450 system ( Sikic et al , 1997 ).…”

The perils of P-glycoprotein inhibition

“…11 In rats bearing human clinical trials, enhanced myelosuppression was found when progesterone was combined with doxorubicin or when Walker 256 carcinosarcoma, hepatic arterial infusion of a combination of doxorubicin and verapamil resulted in encyclosporine was used in combination with etoposide, epidoxorubicin, or doxorubicin. [6][7][8] In one of these studies, no change hanced cytotoxicity to tumor tissue without aggravating the side effects induced by doxorubicin or resulting in increased in doxorubicin pharmacokinetics was observed, suggesting that the enhanced myelosuppression was caused by interfer-doxorubicin accumulation in the liver or heart. 12 A phase 1 clinical trial of intrahepatic verapamil and doxorubicin to ence with the P-glycoprotein extrusion pump on hematopoietic stem cells.…”

“…Cyclosporine de-fects or altered doxorubicin pharmacokinetics, although doxorubicin-mediated myelosupression was dose-limiting. 13 creased clearance and increased the volume of distribution of etoposide and doxorubin, 6,8 suggesting increased retention Chemosensitization trials involving hepatic cancer should continue to include pharmacokinetic investigation of both of these drug in tissues. Verapamil has also been shown to decrease doxorubicin clearance.…”