Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood–Brain Barrier

• Published in: Neurochemical research 2022-03, Vol.47 (3), p.634-643
• Main Authors: Shan, Yuheng, Cen, Yuying, Zhang, Yanjin, Tan, Ruishu, Zhao, Jiahua, Nie, Zhiyong, Zhang, Jiatang, Yu, Shengyuan
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibiotics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biochemistry; Biological Transport - physiology; Biomedical and Life Sciences; Biomedicine; Blood levels; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - metabolism; Ceftriaxone; Ceftriaxone - pharmacology; Cell Biology; Cyclosporin A; Efflux; Glycoproteins; Inhibitors; Intravenous administration; Mice; Microdialysis; Neurochemistry; Neurology; Neurosciences; Original Paper; P-Glycoprotein; Penetration; Pretreatment; Rats; Substrates; Verapamil
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-021-03472-1

Recent studies indicate that inhibition of the efflux transporter P-glycoprotein (P-gp) at the blood–brain barrier (BBB) may represent a putative strategy to increase the BBB penetration of several antibiotics. Therefore, the present study aimed to investigate the effect of P-gp inhibition on the transport of ceftriaxone (CFX) across the BBB. Blood and brain microdialysis in rats was used to monitor blood and brain unbound CFX concentrations following intravenous administration (50 mg/kg), with or without pretreatment with one of the P-gp inhibitors, cyclosporin A (6.25, 12.5, 25 mg/kg) or verapamil (5, 10, 20 mg/kg). An inhibitory effect was demonstrated by an increase in the ratio of unbound brain to unbound blood concentration (K p.uu.brain ) of CFX. The concentrations of CFX in blood and brain from 0 to 180 min after intravenous administration (CFX, 50 mg/kg) ranged from 3 to 40 μg/ml and 1 to 10 μg/ml, respectively. The K p.uu.brain of CFX was 24.74 ± 1.34%. Pretreatment with cyclosporin A increased the brain concentration and the K p.uu.brain of CFX in a dose-dependent manner. However, pretreatment with verapamil increased the brain concentration of CFX but not the K p.uu.brain . The present data shows that CFX might be a substrate of P-gp efflux transporter at the BBB and P-gp inhibition might enhance the brain concentration of CFX. Future studies involving more selective P-gp inhibitors or knockout mouse models should be conducted to specifically elucidate the impact of P-gp inhibition on penetration of CFX across the BBB.