Comparative pharmacokinetics of cyclosporine and NVa2-cyclosporine in dogs.
Raman VenkataramananS TodoIman ZaghloulStephen V. LynchIgal KamR J PtachcinskiG J BurckartThomas E. Starzl
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Ciclosporin
Cyclosporins
Nephrotoxicity
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The pharmacokinetic interaction between TAK-044 (cyclo[D-α-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-alanyl-L-α-aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium, CAS 157380-72-8) and ciclosporin (CAS 59865-13-3) was investigated after concomitant intravenous (i.v.) administration in rats. After i.v. administration of 14C-labeled TAK-044 ([14C]TAK-044 alone at a dose of 3 mg/kg, the radioactivity concentration in the plasma was 1.65 µg/ml at 5 min and decreased biphasically with half-lives of 0.09 h and 0.39 h. AUC0–1h was 0.38 µg · h/ml. The pharmacokinetics of [14C]TAK-044 were affected dose-dependently by coadministration with ciclosporin. The AUC value for [14C]TAK-044 was increased 5-and 14-fold by the coadministration with cyclosporin at doses of 3 and 10 mg/kg, respectively. On the other hand, TAK-044 (3 and 10 mg/kg) did not change the pharmacokinetic parameters for ciclosporin (3 mg/kg). Biliary excretion is the major elimination route for both TAK-044 and cyclosporin. Ciclosporin delayed biliary excretion of [14C]TAK-044 in a dose-dependent manner, which might be due to inhibition of process(es) of hepato-biliary excretion of TAK-044. In conclusion, the AUC values for TAK-044 in rats are increased dose-dependently by coadministration with ciclosporin. Therefore, it may be necessary to adjust the dosage of the TAK-044 in combination with ciclosporin in the course of the first clinical trials.
Ciclosporin
Cyclosporins
Endothelin receptor antagonist
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Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645+/-236 mL/h/kg, 546+/-101 mL/h/kg (P = .01), and 540+/-104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.
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IntroductionCalcineurin inhibitors (CNIs) are maintenance immunosuppressive drugs that have been used as the main therapy for organ transplantation for many years.Of the CNIs, cyclosporine (CYA) and tacrolimus (TAC) are used in clinical practice.The CYA binding protein is cyclophilin and that of TAC is FK-binding protein (FKBP), but both drugs have same mechanism of action: the inhibition of interleukin 2 (IL-2) production by binding the binding protein complex to calcineurin (CN).It is thought that the area under the concentration time curve (AUC) for both drugs may be the pharmacokinetic (PK) parameter that is the most associated with clinical effect.However, oral CYA administration gave a blood concentration-time curve with a high CYA peak concentration (C p ), and oral TAC showed a gradual blood concentration-time curve, keeping at the minimum of the therapeutic range; both drugs vary significantly in their pharmacokinetics 1) .The C p of CYA has increased since the Neoral® preparation of CYA was used, compared with Sandimmune®, whereas the C p of TAC decreased since using a sustained release preparation; thus the differences between CYA and TAC are considerable 2) .Although the optimal pharmacokinetics of both drugs may be similar to those of other drugs with the same mechanism of action, no conclusions have been reached on whether the peak blood concentration, or a specific maintained blood concentration, is required for CNI pharmacokinetics, even if both drugs show identical AUCs.In addition, although CYA and TAC are similar CNI drugs, there are differences in the recommended monitoring points of CYA and TAC; these points are the C 2 level (the blood concentration 2 h after oral administration), which mainly reflects C p, and the trough concentration (C t ) [3][4][5][6][7][8] , respectively 9- 11) .To solve these problems, it is necessary to consider comprehensively not only AUC, but also C p , C t , and time above the minimum effective concentration (%T > MEC). We disuss the optimal pharmacokinetics of CNIs by comparing various aspects of CYA and TAC. Which parameter is the most closely associated with clinical results? CyclosporineIt is a well-known fact that C t is associated with clinical effect.As when the C t become higher, the AUC and the Ct p are consequently higher.it is not surprising that C t , C p , and www.intechopen.com
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Cyclosporins
Nephrotoxicity
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Mycophenolate mofetil (MMF) is almost completely absorbed from the gut and is rapidly de-esterified into its active drug, mycophenolic acid (MPA). The main metabolite is glucuronidated MPA (MPAG), which is excreted into bile and undergoes enterohepatic recirculation. Studies in healthy volunteers treated with cholestyramine show that interruption of the enterohepatic recirculation decreases MPA exposure by approximately 40%. Published data show a difference in mycophenolic acid plasma concentrations between kidney transplant recipients treated with MMF plus cyclosporine (CsA) and those treated with MMF plus tacrolimus (TRL). However, the interpretation of these data is complicated by interpatient differences in variables that may influence MMF pharmacokinetics (e.g., underlying disease, co-medication, and time since transplantation). To understand the influence of TRL and CsA on MMF pharmacokinetics (PK) more completely, the authors eliminated confounding variables in clinical studies by performing drug interaction studies in inbred rats. To achieve a steady state, 3 groups of Lewis rats (n = 8 per group) were treated once daily with oral CsA (8 mg/kg), TRL (4 mg/kg), or placebo on days 0–6 before all rats began once-daily oral treatment with MMF (20 mg/kg) on day 7. Combined treatment with either MMF + CsA, MMF + TRL, or MMF + placebo was continued for 1 week (days 8–14). Thereafter, CsA and TRL treatments were stopped but MMF treatment was continued on days 14–21. Blood was sampled during the 24 hours subsequent to dosing on day 7 (after the first MMF dose), on day 14 (after multiple MMF doses) and on day 21 (after CsA/TRL washout). Rats in the MMF + TRL group and in the MMF + placebo group showed a second peak in the MPA-PK profiles consistent with enterohepatic recirculation of MPA. The MPA-PK profiles for the MMF + CsA–treated animals did not show a second MPA peak. On Day 14, the mean plasma MPA-AUC0–24 hours for the CsA-treated animals was significantly less than MPA exposures for rats in the MMF + TRL– and the MMF + placebo–treated groups. Furthermore, in contrast to results from other investigators, co-administration of CsA and MMF significantly increased MPAG-AUC0–24 hours. Serum creatinines did not differ among rats in the three groups. CsA but not TRL decreased MPA plasma levels and increased MPAG-AUC0–24 hours. These data suggest that CsA inhibits MPAG excretion into bile and offer an explanation for the well-known increased MPA exposure in organ transplant patients caused by conversion from CsA-to TRL-based immunosuppression.
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Enterohepatic circulation
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Cholestyramine
Therapeutic Drug Monitoring
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The effects of berberine (BBR) on the pharmacokinetics of ciclosporin A (CsA) were examined in healthy volunteers. Six healthy male volunteers were orally treated with 0.3 g BBR, twice daily for 10 days. Pharmacokinetic investigations on CsA at 6 mg/kg were done both before and at the end of the BBR treatment period. Another six healthy male volunteers were involved in the pharmacokinetic study with 3 mg CsA/kg, in which the subjects orally received the second single dose of 3 mg CsA/kg, followed by a single oral dose of 0.3 g BBR. The blood CsA concentrations were determined by fluorescence polarization immunoassay. In the pharmacokinetic study with 6 mg CsA/kg, BBR caused no significant changes in the pharmacokinetic parameters of CsA. However, in the trial with 3 mg CsA/kg, the average percentage increase in area under the blood concentration-time curve of CsA was 19.2% (P < 0.05) and the mean C12 increased to 123 microg/l from 104 microg/l (P < 0.05), without altering elimination half-life (t(1/2)), maximum blood drug concentration (Cmax), time to Cmax (tmax), apparent oral clearance (CL/F). The present results suggest that BBR can increase the oral bioavailability of CsA at the dosage of 3 mg/kg. The BBR-mediated increase in CsA bioavailability may be partly attributed to a decrease in liver and/or intestinal metabolism through the inhibition of CYP3A4 in the liver and/or gut wall. The BBR-induced increase in emptying time of stomach and small intestine might be another reason for the increase in CsA bioavailability. However, the speculation should be proved by further investigation.
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Cyclosporin A (CsA) has been shown to increase the sensitivity of multidrug resistant (MDR) cells to chemotherapeutic agents. Although the concentration of drug required to produce this effect is clinically achievable, the use of this drug would be hampered by significant immunosuppression. We report a comparison of the effects of 11-methyl-leucine cyclosporin (11-met-leu CsA), a non-immunosuppressive homolog to the parent drug, on MDR cell lines. Both cyclosporins sensitized resistant cell lines to doxorubicin, including P388 murine leukemia and GM 3639 human T-cell leukemia. The action of the cyclosporins was more pronounced with resistant cells than with sensitive ones. 11-Met-leu CsA was less potent than, but equally effective as, the parent drug. Both agents increased the intracellular accumulation and retention of doxorubicin in MDR cells. The sensitization caused by the cyclosporins was independent of their effects on cyclophilin, calmodulin, and protein kinase C. Furthermore, there were no differences in the binding of labelled CsA to MDR cells compared to the binding to sensitive cells, suggesting that P-glycoprotein was also not the molecular site of action. These studies demonstrate that a non-immunosuppressive cyclosporin can modulate multidrug resistance and suggest its further evaluation for use in clinical trials.
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