• Korean Journal of Clinical Pharmacy
• /
• v.7 no.2
• /
• pp.51-63
• /
• 1997

The effect of cimetidine administration on the pharmacokinetic parameters of cyclosporine were determined in healthy voluteers. This study was performed in 10 volunteers of age ranged 22-48 years and body weight 48-62 kg. This study was performed with cross-over design. Mono cyclosporine and cyclosporine metabolites was extracted from whole blood analysed by fluororescence polarization immune assay (TDX-FLX, Abbott). After coadministration of cimetidine (300 mg) with cyclosporine (300 mg) orally, maximum concentration of mono cyclosporine was significantly increased $1221{\pm}143\;ng/ml\;to\;1562{\pm}184\;ng/ml$ (P<0.05), area under the time curve of cyclosporine (12 hr) also was significantly increased $7478{\pm}829\;ng/ml{\cdot}hr\;to\;9721{\pm}879\;ng/ml{\cdot}hr$ (P<0.05) and absolute baioavailability of cyclosporine was increased $50\pm5.6\%\;to\;57.6\pm6.1\%\;(P<0.05)$ compared to control group. The blood concentrations of cyclopsorine metabolites were significantly decrased (P<0.05) after coadministration of cimetidine. In cimetidine pretreated group, blood mono cyclosporine concentrations were increased significan시y $1220.0\pm203.00\;ng/ml\;to\;1510.0\pm204.00\;ng/ml$ compared with control group (P<0.05). In the mono cyclosporine pharmacokinetic parameter after oral administration absorption rate and maximum concentration were significantly higher in cimetidine coadministered and pretreated group than control group (P<0.05). The ratio of metabolites and mono cyclosporine concentrations was decreased significantly from $70.8\%\;in\;control\;to\;34.8\%$ in coadministration of cimetidine orally. As matter of facts these reults are considered to inhibition of cyclosporine hepatic metabolism and increasing of cyclosporine absorption rate in gastrointestinal tract because of maintaining cyclosporine stability in elevated gastric pH by cimetidine. We considered, it appeares that cimetidine increase bioavailability of cyclosporine by increasing oral absorption and by decreasing hepatic clearance. But the absorption and clearance of cyclosporine was highly variable individually, and therefore we consider that cyclosporine blood level monitoring would be essential in patients with cimetidine co-administration.

• Korean Journal of Clinical Pharmacy
• /
• v.9 no.1
• /
• pp.66-70
• /
• 1999

The effect of circadian rhythm on cyclosporine pharmacokinetics was studied in rabbits after oral administration of 10 mg/kg dose of cyclosporine at 10:00 a.m. and 10:00 p.m. The blood concentration data were subjected to simultaneous computer nonlinear least squares regression analysis using a 1-compartment pharmacokinetic model. The blood concentrations of cyclosporine at 10:00 a. m. were increased significantly during 2-6 hr compared to those at 10:00 p.m. The area under the blood concentration-time curve (AUC) and peak concentration $(C_{max})$ of cyclosporine at 10:00 a.m. were increased significantly compared to those at 10:00 p.m. The mean total body clearance (CL) of cyclosporine at 10:00 a.m. were decreased significantly compared to those at 10:00 p.m. It is reasonable to consider individual circadian rhythm for effective dosage regimen of cyclosporine in therapeutics.

• Biomolecules & Therapeutics
• /
• v.7 no.4
• /
• pp.342-346
• /
• 1999

This study was performed to investigate the effect of cyclosporine (CsA) on glucose tolerance and peripheral insulin sensitivity in normal Sprague-Dawley rats. After daily treament of CsA (10 mg/kg, i.p.) for two weeks, glucose tolerance tests were carried out by the treatment of glucose (Glu, 2 g/kg, i.p.) alone or in conjunction with exogenous insulin (Ins; human regular insulin, 5 U/kg, s.c.) and measured the decrement of area under the time-plasma glucose concentration curve ($AUC_{o\longrightarrow120}$; g.min/ml) by the trapezoidal rule. The rats were divided into three groups (Glu- (Control), Ins+Glu- and CsA+Ins+Glu-, n=7 in each group). The $AUC_{o\longrightarrow120}$ of the CsA+Ins+Glu-group was significantly (p<0.01) lower than that of Glu-group (61.0% of control) and significantly (p<0.05) higher than that of Ins+Glu-group (197.4% of Ins+Glu-). The CsA+Ins+Glu- grou showed higher levels of maximal blood glucose concentration and higher $AUC_{o\longrightarrow120}$ than those of Ins+Glu-group in normal rats. Besides direct pancreatic toxicity of CsA previously reported (Hahn et al., 1972), these results suggest that CsA also make the possibility to induce peripheral insulin insensitivity and glucose intolerance in normal rats.

• Korean Journal of Clinical Pharmacy
• /
• v.28 no.1
• /
• pp.24-29
• /
• 2018

Background: Cyclosporine is an immunosuppressive agent used to treat and prevent graft versus host reaction (GVHR)-a complication associated with stem cell transplantation. This study aimed to develop a population pharmacokinetic model of cyclosporine and investigate factors affecting cyclosporine clearance in pediatric hematopoietic stem cell transplant patients. Methods: A total of 650 cyclosporine concentrations recorded in 65 patients who underwent hematopoietic stem cell transplantation were used. Data including age, sex, weight, height, body surface area (BSA), type of disease, chemotherapy before stem cell transplantation, type of donor, serum creatinine levels, total bilirubin concentration, hematocrit value, and type of concomitant anti-fungal agents and methylprednisolone used were retrospectively collected. Data related to cyclosporine dosage, administration time, and blood concentration were also collected. All data were analyzed using the non-linear mixed effect model; a two-compartment model with first-order elimination was used. Results: The population pharmacokinetic model of cyclosporine using the NONMEM program was as follows: $CL(L/h)=5.9{\times}(BSA/1.2)^{0.9}$, V2 (L) = 54.5, Q (L/h) = 3.5, V3 (L) = 1080.0, $k_a(h^{-1})=0.000377$. BSA was selected as a covariate of cyclosporine clearance, which increased with an increase in BSA. Conclusion: A population pharmacokinetic model for Korean pediatric hematopoietic stem cell transplant patients was developed, and the important factor affecting cyclosporine clearance was found to be BSA. The model might contribute to the development of the most appropriate dosing regimen for cyclosporine. Further studies on population pharmacokinetics should be carried out, prospectively targeting pediatric patients.

• Clinical and Experimental Pediatrics
• /
• v.48 no.5
• /
• pp.476-480
• /
• 2005

Immunosuppressive therapy in pediatric renal transplant recipients is changing consequence of the increasing number of available immunosuppressive agents. The optimal use of immunosuppressive agents requires a thorough understanding of the pharmacokinetic characteristics, but the information on the pharmacokinetic characteristics of these drugs in pediatric transplant recipients is still limited. In general, patients younger than 5 years old show higher clearance rates, therefore the need for higher dosages in younger patients seems evident. By the therapeutic drug monitoring, trough($C_{min}$) and peak level($C_{max}$) are measured and the area under the blood concentration-time curve(AUC), which is taken as being representative of total systemic exposure can be calculated. Cyclosporine A (CSA) has poor bioavailability, which contributes to high inter- and intra-patient pharmacokinetic variability. CSA concentration measured 2 hours after administration($C_2$) has better correlation with the AUC than $C_{min}$ and is an alternative technique that predicts the AUC. Tacrolimus(Tac) has a great deal of inter-individual variability like CSA but intra-individual variability in systemic exposure is considered to be low. Both CSA and Tac are metabolized by a cytochrome P-450 enzyme isoform(CYP3A4). We should consider changing the dosages when CSA or Tac is used in combination with the medicines that inhibit or induce the CYP3A4. In case of steroid-free immunosuppressive therapy, the blood concentration of Tac should be frequently checked and dosage adjustment may be needed.

• The Korean Journal of Nuclear Medicine
• /
• v.23 no.2
• /
• pp.225-230
• /
• 1989

According to the development of monoclonal antibodies against cyclosporine, it became available to replace the conventional polyclonal antibody method with new monoclonal antibody method to measure the blood level of cyclosporine by radioimmunoassay. We compared the results obtained by the two methods: polyclonal antibody and monoclonal antibody method. The results were obtained as follows: 1) We obtained mean value 137.3 ng/ml and CV 16.1% from plasma sample, and mean values 495.7 ng/ml and 1053.8 ng/ml and CVs 19.3% and 17.4% respectively from whole blood sample by polyclonal antibody method. 2) For the two control groups, 100 ng/ml 400 ng/ml each, we obtained that the CVs were 20.2% and 14.0% respectively from plasma sample, and 11 9% and 13.1% respectively from whole blood sample by monoclonal antibody method. In conclusion, we found that cyclosporine RIA was a relatively reliable method to measure blood or plasma concentration. Especially RIA using monocloanl antibody showed less degree of error in measurement compared to polyclonal antibody method.

• YAKHAK HOEJI
• /
• v.42 no.2
• /
• pp.181-186
• /
• 1998

This study was attempted to investigate the pharmacokinetics of cyclosporine (10mg/kg, oral) in rabbits with $CCI_4$ and bile duct ligation-induced hepatic disorder. The area under the curve (AUC) of blood cyclosporine concentration versus time was significantly increased ($CCI_4$-induced hepatic disorder. Elimination rate constant (Kel) was significantly decreased (p<0.05, p<0.01) in rabbits with $CCI_4$ and bile duct ligation-induced hepatic disorder. Volume of distribution (Vdss) and total body clearance (CLtot) were significantly decreased (p<0.01) in rabbits with $CCI_4$-induced hepatic disorder. But Vdss was significantly increased (p4-induced hepatic disorder were 874ng/ml and 2.71 hr, respectively. Cmax and Tmax values in rabbits with bile duct ligation were 105ng/ml and 2.834 hr, respectively. From results of this experiment. It is desirable to do therapeutic drug monitoring of cyclosporine for effective treatment when the cyclosporine is administered to patients with liver disorder m clinical practice.

• Korean Journal of Clinical Pharmacy
• /
• v.13 no.1
• /
• pp.1-4
• /
• 2003

Cyclosporine (CsA) has become well established as a potent immunosuppressive agent in the renal transplantation. However, therapy is complicated by large intraindividual and interindividual variability in pharmacokinetics of CsA and frequent undesirable clinical outcomes such as graft rejection and nephrotoxicity. The objective of this study was to determine the CsA trough blood concentrations that were associated with acute graft rejection and renal toxicity in renal transplant patients. Also, the ability of the current recommendation of therapeutic range for CsA to prevent graft rejections and CsA-associated renal toxicity was assessed. The clinical courses of the patients on CsA as an immusuppressive agent for preventing the graft rejection with renal ransplantation performed at Seoul National University Hospital from January 1995 to September 1998 were retrospectively reviewed. Total of 78 patients were included and three of them were retransplantation cases. Twenty-two acute episodes of rejection were identified, but only 16 episodes were clinically significant. Of these all the episodes occurred during the first month after transplantation except one. Mean daily doses of CsA were $427.2\pm72.1,\;352.6\pm56.8,\;308.62\pm48.3\;and\;268.47.1\;mg$ at posttransplant 1, 3, 6, and 12 months, respectively. Mean CsA whole blood though levels were $259.8\pm36.2,\;238.5\pm39,\;200.8\pm45.8\;and\;161.9\pm25.8\;ng/ml$ at posttransplant 1, 3, 6 and 12 months, respectively. Mean daily doses/weight were $7.9\pm1,\;6.4\pm1,\;5.3\pm0.7\;and\;4.6\pm0.7\;mg/kg$ at posttransplant 1, 3, 6 and 12 months, respectively. CsA doses decreased significantly as months progressed (p<0.001). During the first month after transplantation, only $12.5\%$ of the patients in rejection group had CsA concentration in therapeutic range, and 87.5, 93.8, and $100\%$ were within the therapeutic range at posttransplant 3, 6, and 12 months, respectively. These results suggested that CsA concentrations of $250\sim300\;ng/ml$ might be appropriate for preventing the acute rejection during the first posttransplant month.

• Journal of Chest Surgery
• /
• v.26 no.3
• /
• pp.224-227
• /
• 1993

We experienced one case of orthotopic cardiac transplantation in a patient with end stage dilated cardiomyopathy. This 50 year-old female recipient was suffered from NYHA functional class IV cardiac failure and dependent upon intravenous inotropic support for 2 months [recipient category 1]. Her preoperative condition was grave with left ventricular ejection fraction of 20% and estimated systolic pulmonary arterial pressure [from Doppler study] was 50mmHg. The brain-dead donor was 31 year-old male with head trauma. The body sizes [weight, height] of the donor/recipient were 70 Kg, 165 cm / 43 Kg, 160 cm and appropriately overmatched. Preoperatively, identical ABO/Rh blood group [A+] and nonreacting HLA crossmatching were confirmed. On November 11 1992 cardiac transplantation was performed without complication. Multiple organ procurement team and heart transplantation team were organized the operation schedule appropriately to minimize the ischemic time. The pump time was 126 minutes and aortic crossclamping time of recipient heart was 73 minutes and, as a result, total ischemic time of the transplanted heart was 75 minutes. Postoperatively, the vital signs were stable with minimal inotropic support. The immunosuppressive therapy was commenced from preoperatively and cyclosporine, azathioprine, and corticosteroid were used as a combination therapy as scheduled and monitored with blood drug concentration, WBC count, renal function and most importantly regular endomyocardial biopsy.Now, 5 months after transplantation, the patient is in NYHA functional class II with minimal cardiac drug support.