A synergistic effect of P-glycoprotein (P-gp)/Abcb1a and breast cancer resistance protein (Bcrp)/Abcg2 was reported to limit the brain penetration of their common substrates. This study investigated this based on pharmacokinetics using Mdr1a/1b(Ϫ/Ϫ), Bcrp(Ϫ/Ϫ), and Mdr1a/1b(Ϫ/Ϫ)/ Bcrp(Ϫ/Ϫ) mice. Comparison of the brain-and testis-toplasma ratios (C brain /C plasma and C testis /C plasma , respectively) of the reference compounds quinidine and dantrolene for P-gp and Bcrp, respectively, indicates that impairment of either P-gp and Bcrp did not cause any change in the efflux activities of Bcrp or P-gp, respectively, at both the bloodbrain barrier (BBB) and blood-testis barrier (BTB). The C brain / C plasma and C testis /C plasma of the common substrates erlotinib, flavopiridol, and mitoxantrone were markedly increased in Mdr1a/1b(Ϫ/Ϫ)/Bcrp(Ϫ/Ϫ) mice even compared with Mdr1a/1b(Ϫ/Ϫ) and Bcrp(Ϫ/Ϫ) mice. Efflux activities by P-gp and Bcrp relative to passive diffusion at the BBB and BTB were separately evaluated based on the C brain /C plasma and C testis /C plasma in the knockout strains to the wild-type strain. P-gp made a larger contribution than Bcrp to the net efflux of the common substrates, but Bcrp activities were also significantly larger than passive diffusion. These parameters could reasonably account for the marked increase in C brain /C plasma and C testis /C plasma in the Mdr1a/1b(Ϫ/Ϫ)/ Bcrp(Ϫ/Ϫ) mice. In conclusion, the synergistic effect of P-gp and Bcrp on C brain /C plasma and C testis /C plasma can be explained by their contribution to the net efflux at the BBB and BTB without any interaction between P-gp and Bcrp.It is well accepted that the penetration of xenobiotic compounds into the brain and testis is restricted by the blood-brain barrier (BBB) and blood-testis barrier (BTB), respectively. The BBB is formed by brain capillary endothelial cells, whereas, in addition to endothelial cells, myoid and Sertoli cells form the BTB (Bart et al., 2002;Kusuhara and Sugiyama, 2005). Tight junctions between adjacent cells in the BBB and BTB are highly developed and limit the penetration of substances via the paracellular route. Moreover, drug transporters act as active barriers to limit the tissue penetration of substrates from the blood by extruding them back into the blood in the BBB and BTB and, thereby, modulating pharmacological or adverse reactions. It has been shown that ATP binding cassette (ABC) transporters, which are known to mediate resistance to anticancer drugs and antiviral drugs, are expressed in the BBB and BTB. These include P-glycoprotein (P-gp/MDR1/ABCB1), breast cancer resistance protein (BCRP/ABCG2), multidrug resistance-associated protein (MRP)-1/ABCC1, MRP2/ABCC2, MRP4/ABCC4, and MRP5/ABCC5 (Leggas et al., 2004;Zhang et al., 2004;Lee et al., 2005). In particular, P-gp is a well known transporter that plays a pivotal role in barrier function, and disruption of the Mdr1a gene, a predominant isoform expressed in the barriers, causes accumulation of a number of its substrates (S...

UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.

This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (C u,brain ) by the concentration in the cerebrospinal fluid (CSF) (C u,CSF ) in rats. C u,brain is obtained as the product of the total brain concentration and unbound fraction in the brain (f u,brain ) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concentration ratio (K p,uu,CSF/brain ) compared with non-P-gp and non-Bcrp substrates. K p,uu,CSF/brain values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/ 1b(Ϫ/Ϫ) and Bcrp(Ϫ/Ϫ) mice, respectively. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, K p,uu,CSF/brain values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/ 1b(Ϫ/Ϫ)/Bcrp(Ϫ/Ϫ) mice, but only moderately or weakly in Mdr1a/1b(Ϫ/Ϫ) mice and negligibly in Bcrp(Ϫ/Ϫ) mice. In conclusion, predictability of C u,brain by C u,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. C u,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of C u,brain for lipophilic compounds.