title: In vitro and in vivo evidence for amphotericin B as a P-glycoprotein substrate on the blood-brain barrier.
abstract: Amphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cells in vitro was significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected with Cryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0; P < 0.05) and 30 min (5.2 versus 2.8; P < 0.05) after administration of verapamil or 45 min (6.0 versus 3.9; P < 0.05) and 60 min (5.4 versus 3.8; P < 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P < 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Ji-Qin
authors.initials: JQ
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Shao
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Rui-Ying
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Cao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yun-Qiu
authors.initials: YQ
authors.lastname: Yu
authors.affiliation: Institute of Clinical Medicine Research, Chinese-Japanese Friendship Hospital, Beijing, China.
authors.forename: Jin-Ning
authors.initials: JN
authors.lastname: Lou
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Yan-Qiong
authors.initials: YQ
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Hua-Zhen
authors.initials: HZ
authors.lastname: Zhao
authors.affiliation: Clinical Mycology Laboratory, Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiang-Qiang
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Weng
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China jiangchen@shmu.edu.cn zhulp@fudan.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China jiangchen@shmu.edu.cn zhulp@fudan.edu.cn.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Zhu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000666:Amphotericin B / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007276:Injections, Intraventricular; D017964:Itraconazole / Q000494:pharmacology; D008297:Male; D051379:Mice; D016019:Survival Analysis; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D017964:Itraconazole; D000666:Amphotericin B; D014700:Verapamil