The Role of Cytochrome P450 3A5 Enzyme on the Metabolism of Tacrolimus in Rats

Year 2017, Volume: 1 Issue: 2, 53 - 56, 01.06.2017

Özlem Gür Mukaddes Gümüştekin Nergiz Murat Sedef Gidener

https://doi.org/10.5152/jbachs.2017.84

Cited By: 1

Abstract

Purpose: The present study was designed to determine the effect ratio of CYP3A5 on the metabolism of tacrolimus that is used as an immunosuppressant for tissue transplantation.Methods: To determine the role of CYP3A4 and CYP3A5 on tacrolimus metabolism, rats were divided into five groups as: group 1 control group, tacrolimus only 1 mg/kg i.v. , group 2 pretreated with ritonavir 5 mg/kg, i.v. 1 h before administration of tacrolimus , group 3 pretreated with indinavir 10 mg/kg, i.v. 1 hour before administration of tacrolimus , groups 4 and 5, in addition to the protocol of groups 2 and groups 3. Dexamethasone 100 mg/kg, p.o. was administered for 2 days before the experimental study to each group. To estimate the area under curve AUC of tacrolimus, the blood samples were collected after 15, 30, 60, 75, and 90 min and after 2, 3, 4, 8, and 24 h, and MEIA method was used to determine whole blood levels of tacrolimus.Results: Although the AUCs of tacrolimus in group 2 533.5±139.85 ng.h/mL and group 3 3428±683 ng.h/mL were higher than the control group 394±127 ng.h/mL , the only significant difference was found in ritonavir pretreated group group 3 . In dexamethasone pretreated groups, the AUC values were similar to control group.Conclusion: These results suggest that the role of CYP3A5 enzyme has to be taken into account for probable drug interactions and sufficient immunosuppression in patients who are treated with tacrolimus

Keywords

AUC, CYP3A5, drug metabolism, rat, tacrolimus

References

• Hashimato T, Sasa H, Shimomura I, Inui KI. Effects of intestinal and hepatik metabolism on the bioavailability of tacrolimus in rats. Pharm Res 1998; 15:1609-1613. [CrossRef]
• Kagayama A, Tanimoto S, Fujisaki J, et al. Oral absorption of FK506 in rats. Pharm Res 1993; 10:1446-1450. [CrossRef]
• Plosker GL, Foster RH. Tacrolimus: a further update of its pharma- cology and therapeutic use in the management of organ transplan- tation. Drugs 2000; 59:323-389. [CrossRef]
• Yasuda K, Lan LB, Sanglard D, et al. Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J Pharmacol Exp Ther 2002; 303:323-332. [CrossRef]
• Cholerton S, Daly AK, Idle JR. The role of individual human cyto- chromes p450 in drug metabolism and clinical response. Trends Pharmacol Sci 1992; 13:434. [CrossRef]
• Christians U, Schmitz V, Haschke M. Functional interactions be- tween P-glycoprotein and CYP3A in drug metabolism. Expert Opin Drug Metab Toxicol 2005; 1:641-654. [CrossRef]
• Salphati L, Benet LZ. Modulation of p-glycoprotein expression by cytochrome P450 3A inducers in male and female rat livers. Bio- chem Pharmacol 1998; 55:387-395. [CrossRef]
• Yumoto R, Murakami T, Sanemasa M, et al. Pharmacokinetic inter- action of cytochrome p450 3A-related compounds with rhodamine 123, a p-glycoprotein substrate, in rats pretreated with dexametha- sone. Drug Metab Dispos 2001; 29:145-151.
• Huang L, Wring SA, Woolley JL, et al. Induction of P-glycoprotein and cytochrome P450 3A by HIV protease inhibitors. Drug Metab Dispos 2001; 29:754-760.
• Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome p450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 1996; 277:423-431.
• Chiba M, Hensleigh M, Lin JH. Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Biochem Pharmacol 1997; 53:1187-1195. [CrossRef]
• Lin JH, Chiba M, Balani SK, et al. Species differences in the pharma- cokinetics and metabolism of indinavir, a potent human immunode- ficiency virus protease inhibitor. Drug Metab Dispos 1996; 24:1111-1120.
• Koudriakova T, Iatsimirskaia E, Utkin İ. Metabolism of the human immunodefiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome p450 3A4/3A5: mechanism - based inactivation of cytochrome p4503A by ritonavir. Drug Metab Dispos 1998; 26:552-561.
• Jain AB, Venkataramanan R, Eghtesad B, et al. Effect of coadminis- tered lopinavir and ritonavir (Kaletra) on tacrolimus blood concen- tration in liver transplantation patients. Liver Transpl 2003; 9:954- 960. [CrossRef]
• Ernest CS, Hall SD, Jones DR. Mechanism-based inactivation of CY- P3A by HIV protease inhibitors. J Pharmacol Exp Ther 2005; 312:583- 591. [CrossRef]
• Hardy G, Stanke-Labesque F, Contamin C, et al. Protease inhibitors and diltiazem increase tacrolimus blood concentration in a patient with renal transplantation: a case report. Eur J Clin Pharmacol 2004; 60:603-605. [CrossRef]
• Zahir H, McCaughan G, Gleeson M, et al. Changes in tacrolimus dis- tribution in blood and plasma protein binding following liver trans- plantation. Ther Drug Monit 2004; 26:506-515. [CrossRef]
• Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentra- tion-to-dose ratio in renal transplant recipients. Transplantation 2003; 76:1541-1542. [CrossRef]
• Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004; 78:1182-1187. [CrossRef]
• Op den Buijsch RA, Christiaans MH, Stolk LM, et al. Tacrolimus phar- macokinetics and pharmacogenetics: influence of adenosine tri- phosphate-binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol 2007; 21:427-435.[CrossRef]