CYP3A4 and P-Glycoprotein Activity in Healthy Controls and Transplant Patients on Cyclosporin vs. Tacrolimus vs. Sirolimus

Abstract

This study aimed to determine the impact of maintenance immunosuppressive therapy with cyclosporin A (CsA), tacrolimus (FK506) and sirolimus (Rapa) on the in vivo activity of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) in renal transplant patients. The activity of these four elimination pathways was measured by the recently validated intravenous (iv) and per oral (po) 14 C erythromycin breath and urine test. In addition, overall hepatic P450 activity was measured by the 13 C aminopyrin breath test. Three groups of stable renal transplant patients on maintenance therapy with corticosteroids (CS) and mycophenolate mofetil (MMF) plus either CsA or FK506 or Rapa were examined. A significant increase in intestinal CYP3A4 activity and a significant decrease in hepatic and intestinal PGP activity was seen in patients on CsA in comparison with those on FK506 or Rapa (p < 0.01). A similar analysis in six healthy volunteers at baseline and after intake of CsA, FK506 and Rapa confirmed the results seen in the patients. There was no difference in CYP3A4 and PGP activity in the patients taking either FK506 or Rapa and healthy controls. These data suggest that a different pattern of drug interactions might be expected in patients treated with CsA vs. FK506/Rapa.

Long-term outcome of ketoconazole and tacrolimus co-administration in kidney transplant patients

“…Due to the numerous adverse effects, narrow safety margin and large intra-and inter-individual variability in pharmacokinetics, therapeutic monitoring is mandatory [1][2][3] . The normal pharmacokinetic curve of tacrolimus has a peak-andtrough pattern.…”

“…Due to its narrow therapeutic index, optimal dosing with therapeutic monitoring is necessary. Tacrolimus is mainly metabolized by cytochrome P450-3A in the liver and a substrate of P-glycoprotein, an efflux pump, in both liver and intestine [2,3] . The inhibition of P450-3A and P-glycoprotein can slow down its metabolism and ketoconazole is such a potent inhibitor.…”

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

“…The alteration in these enzymes and proteins affects drug bioavailability and increases the risk for adverse drug reactions (Dreisbach and Lertora 2008;Dreisbach 2009). In transplant patients on cyclosporine-A or tacrolimus, studies have shown changes in both CYP3A4 and P-glycoprotein activity in healthy controls and patients (Lemahieu WP, 2004). In addition to the condition or disease alone regulating enzyme activity and transporter expression, consideration should be applied during treatment for patients on multiple medications (van der Deen M, 2005).…”

Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient

“…For several years, the mammilian target of rapamycin (mTOR) inhibitor, sirolimus (Rapamune®), has also been used as an immunosuppressive drug in organ transplantation. Similar to ciclosporin, it is also metabolized in bowel and liver by cytochrome P450 3A [1] . The main advantage of sirolimus is its virtual lack of nephrotoxicity.…”

“…Both are calcineurin-inhibitors and have the same mode of action. They are mainly metabolized by cytochrome P450 3A4 in bowel and liver [1] . The main side effects of ciclosporin and tacrolimus are renal toxicity, neurotoxicity, arterial hypertension, diabetes mellitus and hyperlipidemia [2] .…”