P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists.

Article

Author: Doran, A C ; McLean, S ; Tingley, F D ; Kajiji, S M ; O'Neill, B T ; Smith, B J

CP-122721 and CP-141938 are potent and selective neurokinin-1 (NK(1)) receptor antagonists with very different brain disposition and potency in models of centrally mediated activity. These investigations sought to determine whether differences in potency were related to differences in P-glycoprotein (P-gp) transport at the blood-brain barrier. Both compounds stimulated ATPase activity of human recombinant MDR1 with similar kinetic parameters. Cell-associated drug concentrations of CP-141938 were 9.4-fold lower in KBV1 cells expressing P-gp compared with KB3.1 control cells. In Madin-Darby canine kidney (MDCK) cells expressing human MDR1, asymmetric transport of CP-141938 was 5-fold higher than in wild-type MDCK cells, whereas no asymmetry was observed with CP-122721. In agreement with these differences in cellular transport, the differences in brain/plasma ratio between mdr1a/b(-/-) and FVB mice 1 h following a 3 mg/kg s.c. dose were 3- and 50-fold for CP-122721 and CP-141938, respectively. The effect of inhibiting P-gp efflux on the effects of these agents was evaluated using GR73632-induced foot tapping in gerbils as a model to measure centrally mediated NK(1) antagonism. When gerbils were pretreated with the P-gp inhibitor MS-073 (50 mg/kg s.c.), there was no effect on the activity of CP-122721 (0.05 mg/kg), whereas the percent reversal for CP-141938 (10 mg/kg) increased from 60 to 100%. In gerbils, the brain/plasma ratio for CP-122721 was unaffected by MS-073 pretreatment, whereas the brain/plasma ratio for CP-141938 brain concentrations increased 13-fold. This suggested that P-gp efflux influences the brain disposition and pharmacologic activity of CP-141938, but not CP-122721. Complete response curves for CP-141938 were then determined with respect to dose, and drug concentration in the plasma and brain in the presence and absence of MS-073 pretreatment. The dose and plasma concentration-response curves of CP-141938 were shifted to the left in the presence of MS-073, yet brain concentrations associated with the response were unchanged. This suggested that once in the brain the interaction of CP-141938 with the NK(1) receptor was not affected by P-gp transport. In conclusion, these studies show that brain disposition and centrally mediated in vivo activity of NK(1) antagonists can be profoundly affected by P-gp transport and that such transport should be considered during the design of new agents.

01 May 1991·Cancer research

Circumvention of multidrug resistance by a newly synthesized quinoline derivative, MS-073.

Article

Author: Fukazawa, N ; Yusa, K ; Sato, W ; Suzuki, T ; Tsuruo, T

Newly synthesized quinoline derivatives were investigated for their efficacy to reverse multidrug resistance (MDR). In this study, one of the most effective quinoline derivatives, MS-073, was compared with verapamil with regard to its ability to overcome MDR in vitro and in vivo. MS-073 at 0.1 microM almost completely reversed in vitro resistance to vincristine (VCR) in VCR-resistant P388 cells. The compound also reversed in vitro VCR, adriamycin (ADM), etoposide, and actinomycin D resistance in ADM-resistant human myelogenous leukemia K562 (K562/ADM) cells, ADM-resistant human ovarian carcinoma A2780 cells, and colchicine-resistant human KB cells. MS-073 administered i.p. daily for 5 days with VCR enhanced the chemotherapeutic effect of VCR in VCR-resistant P388-bearing mice. Increases in life span of 19-50% were obtained by the combination of 100 micrograms/kg of VCR with 3-100 mg/kg of MS-073, as compared to the control. The ability of MS-073 to reverse MDR was remarkably higher, especially at low MS-073 doses, than that of verapamil, both in vitro and in vivo. MS-073 enhanced accumulation of [3H]VCR in K562/ADM cells. Photolabeling of P-glycoprotein with 200 nM [3H]azidopine in K562/ADM plasma membranes was completely inhibited by 10 microM MS-073, indicating that MS-073 reverses MDR by competitively inhibiting drug binding to P-glycoprotein.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	JP	Nihon Schering KK	-
Neoplasms	Preclinical	JP	Nihon Schering KK	-

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