Cyclosporine oral clearance

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Turgeon DK, Normolle DP, Leichtman AB, et al. Erythromycin breath test predicts oral clearance of cyclosporine in kidney transplant recipients. Clin Pharmacol Ther 1992 52 471 178. 

An increase in bioavailability of orally administered cyclosporine A was observed after healthy male volunteers were administered a single dose of 3 mg cyclosporine A followed by a single oral dose of 300 mg of the compound berberine. The increase in area under the time-concentration curve of cyclosporine A was 19.2% no changes in elimination half-life, maximum blood drug concentration, time to maximum concentration, or apparent oral clearance were observed (Xin et al. 2006). Conversely, no changes in bioavailability of orally administered cyclosporine A were observed after healthy male volunteers were administered 300 mg of the compound berberine twice daily for 10 days followed by a single dose of 6 mg cyclosporine A (Xin et al. 2006). 

Acitretin is an oral retinoid that is likely safer than methotrexate or cyclosporine, especially when considering continuous use over many years.21 The initial dose is 25 mg/day which can be increased to a maximum of 75 mg/day if needed.17 When acitretin is used concurrently with phototherapy (ReUVB or RePUVA), there appears to be a synergistic treatment effect, and the number and duration of phototherapy sessions needed to achieve clearance is reduced.21 RePUVA is a well-established... 

Clearance of cyclosporin A and its metabolites proceeds mainly through excretion of bile into faeces. After an oral dose of [3H]cyclosporin A, only 4-6% of the radioactivity is excreted in urine within 96 h. Intact [3H]cy-closporin A contributes only a small proportion of the excreted radioactivity (0.1-0.2% of the dose). The elimination half-life of cyclosporin A from blood, determined by HPLC, amounts to 15.8 8.4 h. 

Recently, bioavailability and clearance data obtained from a crossover study of cyclosporine kinetics before and after rifampin dosing revealed a new understanding of drug metabolism and disposition of the compound (9). Healthy volunteers were given cyclosporine, intravenously and orally, before and after CYP3A (P450 3A) enzymes were introduced by rifampin. As expected, the blood clearance and cyclosporine increased from 0.31 to 0.42 L... 

Cyclosporine absorption is incomplete following oral administration and varies with the individual patient and the formulation used. The ehmination of cyclosporine from the blood is generally biphasic, with a terminal t, of 5-18 hours. After intravenous infusion, clearance is 5-7 mL/min/kg in adult recipients of renal transplants, but results differ by age and patient populations (e.g., slower in cardiac transplant patients, faster in children). Thus, the intersubject variability is so large that individual monitoring is required. 

In kidney transplant patients orally administered 600 mg of St. John s wort daily for 2 weeks in addition to their standard dose of cyclosporine, an increase in the clearance of cyclosporine was observed. The maximum plasma concentration of cyclosporine was reduced by an average of 42% (Bauer et al. 2003). Similar effects were observed in healthy volunteers administered 2.5 mg/kg cyclosporine after daily administration of 900 mg St. John s wort for 14 days (Dresser et al. 2003). 

---