title: Long-term levothyroxine treatment decreases the oral bioavailability of cyclosporin A by inducing P-glycoprotein in small intestine.
abstract: We have noticed that the trough level of blood concentration of cyclosporin A (CyA) tends to be lower in patients receiving long-term oral levothyroxine (LTX) than in patients not receiving LTX. We confirmed this clinical observation in experiments using Wistar rats orally given LTX (8 microg/kg) or saline (control) for 3 weeks, followed by CyA (10 mg/kg). The LTX treatment had little effect on the blood concentrations of CyA after i.v. administration, whereas they were decreased significantly after p.o. administration. After p.o. administration, the value of the area under the blood concentration-time curve from 0 to 24 hr and the bioavailability of CyA in the LTX group were decreased to only about one-fifth and a quarter of those in the control group, respectively. After treatment with LTX, the expression levels of mdr1a, mdr1b and CYP3A2 mRNAs in the duodenum were markedly increased to about twice the control, but in jejunum, ileum and liver the expression levels were little changed. These findings suggest that the absorption of CyA, which occurs mainly from the upper intestine, is reduced as a result of efflux transport via P-glycoprotein induced by LTX. In conclusion, careful monitoring of CyA levels is required in the event of LTX administration to patients receiving immunotherapy with CyA.
authors.affiliation: Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University, Takara-machi, Japan.
authors.forename: Mingji
authors.initials: M
authors.lastname: Jin
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.forename: Miki
authors.initials: M
authors.lastname: Shintani
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokogawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nomura
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000818:Animals; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D014284:Triiodothyronine / Q000097:blood
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D014284:Triiodothyronine; D016572:Cyclosporine; D013972:Thyrotropin; D013974:Thyroxine