1.Transient up-regulation of P-glycoprotein reduces tacrolimus absorption after ischemia-reperfusion injury in rat ileum.
Omae T1, Goto M, Shimomura M, Masuda S, Ito K, Okuda M, Inui K. Biochem Pharmacol. 2005 Feb 15;69(4):561-8. Epub 2004 Dec 25.
Ischemia-reperfusion injury is an unavoidable problem for organ transplantation including small bowel transplantation, and causes a large intra-individual variation of tacrolimus (FK506) pharmacokinetics. Little information is available about the regulation of the intestinal P-glycoprotein expression during tissue regeneration. In the present study, we have examined the molecular and functional variations of ileum P-glycoprotein using rats after ischemia-reperfusion treatment. Morphological study revealed a rapid regeneration of the intestinal wall during 24 h after reperfusion. A reverse transcription-coupled competitive PCR and Western blot analysis revealed that the intestinal expression of P-glycoprotein recovered with time after reperfusion. At 24 h after reperfusion, the ileum P-glycoprotein level was transiently increased to two-fold, and the absorption rate of dihydro-[(3)H]FK506 from in situ ileum loop into portal vein was markedly low in comparison with the control.
2.Factors affecting variability in distribution of tacrolimus in liver transplant recipients.
Zahir H1, McCaughan G, Gleeson M, Nand RA, McLachlan AJ. Br J Clin Pharmacol. 2004 Mar;57(3):298-309.
AIMS: Therapeutic drug monitoring (TDM) of tacrolimus is complicated by conflicting data on the correlation between tacrolimus trough blood concentrations and the incidence of rejection. The aim of this cross-sectional study was to investigate the blood distribution and protein binding of tacrolimus in liver transplant recipients to explore better predictors of clinical outcome.
3.Evaluation, synthesis and characterization of tacrolimus impurities.
Ferraboschi P1, Colombo D, De Mieri M, Grisenti P. J Antibiot (Tokyo). 2012 Jul;65(7):349-54. doi: 10.1038/ja.2012.28. Epub 2012 Apr 18.
Tacrolimus is an immunosuppressant macrolactam of fermentative origin. By means of HPLC, LC-MS and NMR analyses, coupled with the reference standard synthesis, the main impurities of tacrolimus bulk drug samples were identified and their chemical-physical properties reported. Known ascomycin and tautomers I and II were detected. The correct relative retention time HPLC value of 39,40-dihydro tacrolimus was established. The not described 23,24-anhydro derivative was detected and completely characterized. A full characterization of ascomycin and 39,40-dihydro tacrolimus was also reported.