Lowered blood concentration of tacrolimus and its recovery with changes in expression of CYP3A and P-glycoprotein after high-dose steroid therapy.
BACKGROUND
In a living-donor liver transplant patient continuously receiving tacrolimus (FK506), pulse steroid therapy for 3 days caused the blood concentration of FK506 to decrease, followed by a gradual recovery to presteroid levels within 2 weeks. We conducted a study in rats to clarify the mechanism of the changes in the blood concentration of FK506 during and after steroid therapy.


METHODS
Rats were intraperitoneally treated with a low dose (1 mg/kg per day) or a high dose (75 mg/kg per day) of dexamethasone (DEX) for 4 days and, at 1.5 hours after the last dose, were given FK506 (2 mg/kg) intravenously (IV) or orally (PO). Blood concentrations of FK506 and changes in the expression levels of P-glycoprotein and CYP3A2 in the liver and intestine were monitored.


RESULTS
In the low-dose DEX group, the blood concentrations of FK506 after PO administration of FK506 were significantly lowered compared with those in the untreated group, while there was no such difference after IV administration. In the high-dose DEX group, the blood concentrations of FK506 after either IV or PO administration were significantly lowered. Consequently, the bioavailability of FK506 was decreased by DEX treatment, and the total clearance was significantly increased by high-dose DEX treatment. The pharmacokinetic parameters gradually recovered within 2 weeks after high-dose DEX treatment. In the high-dose DEX group, the protein levels of P-glycoprotein and CYP3A2 in the liver and intestine increased just after the treatment then decreased to normal levels within 2 weeks.


CONCLUSIONS
Our results indicate that the decrease in the blood FK506 concentration caused by high-dose steroid therapy is a consequence of the induction of P-glycoprotein and CYP3A in the liver and intestine, and these changes were reversed within 2 weeks after cessation of steroid therapy.
Shimada
Tsutomu
T
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, Kanazawa, Japan.
Terada
Ai
A
Yokogawa
Koichi
K
Kaneko
Hiroko
H
Nomura
Masaaki
M
Kaji
Kyosuke
K
Kaneko
Shuichi
S
Kobayashi
Ken-Ichi
K
Miyamoto
Ken-Ichi
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood*; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000097:blood*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus