Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B.
The trough level of blood concentration of cyclosporin A (CyA) in a patient receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). This clinical observation was confirmed experimentally in Wistar rats intravenously given AMB (1.5 or 3.0 mg/kg) or saline (control) for 4 days, followed by CyA (10 mg/kg). The blood concentration of CyA after i.v. or p.o. administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0 mg/kg AMB treatment was decreased to 67% or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in the duodenum to about three times the control, and expression of CYP3A2 mRNA in the liver was increased to about twice the control. The P-gp and CYP3A2 proteins were increased significantly. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased first-pass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. It is suggested that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA.
Ishizaki
Junko
J
Department of Clinical Pharmaceutics, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Japan.
Ito
Satsuki
S
Jin
Mingji
M
Shimada
Tsutomu
T
Ishigaki
Tamae
T
Harasawa
Yukiko
Y
Yokogawa
Koichi
K
Takami
Akiyoshi
A
Nakao
Shinji
S
Miyamoto
Ken-ichi
K
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000284:Administration, Oral; D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood*; D051544:Cytochrome P-450 CYP3A; D004336:Drug Antagonism; D004386:Duodenum / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood*; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000666:Amphotericin B; D001189:Aryl Hydrocarbon Hydroxylases; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C465260:Cyp3a2 protein, rat