Failing to keep this in mind, may lead to unnecessary biopsies and misdirected therapies. Do you consider this factor in your clinical practice as a routine while tapering steroid dosage after renal transplantation? Your participation will be very much valued. Many thanks.
According to one study from Netherlands, steroid withdrawal resulted in modest increases in tacrolimus levels. See "Increase in tacrolimus trough levels after steroid withdrawal." Elly M van Duijnhoven et al, Transplant International (impact factor: 2.92). 11/2003; 16(10):721-725. ABSTRACT:
Although there are experimental reports of cytochrome P450 3A4 iso-enzyme (CYP3A4) induction by glucocorticoids, there are no clinical reports about an interaction between tacrolimus and steroids. Therefore, tacrolimus trough level and dose were compared after dose-normalization before and after withdrawal of prednisolone. After withdrawal of 5 mg prednisolone, the median tacrolimus dose-normalized level increased by 14% in the retrospective ( n=54), and by 11% in the prospective ( n=8) part of the study. After withdrawal of 10 mg, this increase was 33% ( n=30) and 36% ( n=14), respectively. An additional pharmacokinetic part of the study ( n=8) revealed an 18% increase in AUC ( P=0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced metabolism after steroid withdrawal. The significant increase in tacrolimus exposure after steroid withdrawal may on the one hand counteract the reduction in immunosuppression intended by steroid withdrawal, and, on the other hand, may result in an increase of serum creatinine which could be misinterpreted as rejection.
Cytochrome P-450 3A enzymes are responsible for biotransformation of tacrolimusin man (Drug Metab Dispos. 1992 Sep-Oct;20(5):753-61). There are clearly functional interactions between transporter proteins such as P-glycoprotein and CYP3A in drug metabolism (Ther Drug Monit. 2004 Apr;26(2):104-6). Most drug drug interactions occur through P-glycoprotein and other transporter proteins . Steroids are potent inducers of P-glycoprotein, and the effect will enhance the tacrolimus clearance, depending on the genetics of the steroid effect on the transporter proteins, but not as much on tacrolimus (Br J Clin Pharmacol. 2004 Nov;58(5):548-53.). We published on a relationship between the steroid dose and the dose-normalized tacrolimus exposure as early as 1997 (Nephrol Dial Transplant. 1997 Aug;12(8):1668-71). Statistically, there clearly should be a reduction of the tacrolimus clearance with steroid withdrawal. In two recent paediatric renal transplant recipients, the effect was dramatic, with a dose reduction from 6 mg PO BID to 1 mg PO BID for the same dose-normalized exposure in one patient who weaned herself off steroids completely. The problem is that nobody can predict just how strong the effect will be. As such, even with a Baysian approach, it will be impossible to come up with an algorithm for all patients without having a genetic marker for the magnitude of the steroid-induced induction of the transporter proteins. But to answer the question, yes, we routinely factor in a reduction in the clearance with steroid tapering over time.
Many thanks to you both for your excellent responses and time. Apologise for the delay of several years in my acknowledgement. I am observing the effects of reduction of steroids on the tacrolimus and serum creatinine levels as discussed above routinely. Being aware of these effects has certainly helped in avoiding unnecessary investigations on my patients.
Thanks