Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

Tafazoli, Ali

doi:10.2217/imt.15.47

Cited by 16 publications

(20 citation statements)

References 182 publications

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“…Given the narrow therapeutic index, it may need routine therapeutic monitoring in case of the transplant rejection and toxic reaction. [30,31] It may frequently co-administered with many compound preparations including active ingredient BG for exerting antihepatitis, anti-inflammatory and antiviral effects. [32,33] A clear and detailed understanding of their propensity for drug-drug interactions (DDIs) is required before their concomitant use in transplantation population.…”

Section: Discussionmentioning

confidence: 99%

Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats

Tian

Chang

Wei

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives To investigate the effects of multiple doses of baicalin (BG) on the pharmacokinetics of ciclosporin (CsA) in rats and the potential mechanisms. Methods Pharmacokinetic parameters of CsA were determined in male rats after administration of CsA (3 mg/kg, i.g. or i.v.) to rats in the presence and absence of BG (80 mg/kg, i.g. or i.v.) for 7 days. The livers and intestines of rats were isolated and the CYP3A and p‐glycoprotein (P‐gp) expression were analysed. The effect of BG on the intestinal absorptive behaviour of CsA was also investigated using in‐vitro everted rat gut sac model. Key findings Baicalin (80 mg/kg, i.v., 7 days) had no effect on the intravenously administered CsA. However, BG (80 mg/kg, i.g., 7 days) significantly decreased the Cmax, AUC0–t and AUC0–∞ of orally administered CsA by 38, 26 and 25%, respectively (P < 0.01 or P < 0.05). Further study revealed that the expression of P‐gp in intestine increased in oral multiple doses of BG‐treated rats. The in‐vitro everted rat gut sac model demonstrated BG (10 μm) significantly decreased the absorption of CsA (10 μm) in intestine (P < 0.05). Conclusions Multiple doses of BG decreased the oral bioavailability of CsA in rats significantly, which may be mainly attributable to inhibition of absorption of CsA in intestine and induction of P‐gp. The interaction between BG and CsA may occur when BG and CsA were co‐administered for long‐term use. The dosage adjustment and blood concentration monitoring of CsA may be required in clinic.

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Section: Discussionmentioning

confidence: 99%

Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats

Tian

Chang

Wei

et al. 2019

Journal of Pharmacy and Pharmacology

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“…Cyclophilins are a family of proteins present in vertebrates and other organisms. They bind to CsA, an immunosuppressant that is commonly used to suppress rejection after organ transplantation ( 19 – 20 ). The molecular mechanisms of CsA-induced β cell apoptosis probably involve the downregulation of cyclophilins.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of peptidyl‑prolyl cis‑trans isomerase B mediates cyclosporin A‑induced apoptosis of islet β cells

Wei

Zhu²,

Feng

et al. 2018

Exp Ther Med

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Cyclosporin A (CsA) is widely used as an immunosuppressor in the context of organ transplantation or autoimmune disorders. Recent studies have revealed the detrimental effects of CsA on insulin resistance and pancreatic β cell failure; however, the molecular mechanisms are unknown. The present study sought to confirm the associations between CsA and β cell failure, and to investigate the roles of proinsulin folding and endoplasmic reticulum (ER) stress in CsA-induced β cell failure. The viability of MIN6 cells treated with CsA was evaluated with MTT assay. Expression levels of insulin, peptidyl-prolyl cis-trans isomerase B (PPIB), cleaved caspase-3, phospho-protein kinase R (PKR)-like endoplasmic reticulum kinase (p-PERK), PKR-like endoplasmic reticulum kinase (PERK), binding immunoglobulin protein (BIP), and C/EBP homologous protein (CHOP) were detected via reducing western blot assay. Non-reducing western blot analysis was performed to examine the expression of misfolded proinsulin peptides. The proliferation of MIN6 cells was not inhibited by CsA at concentrations <1 µmol/l. CsA treatment resulted in the decreased expression of insulin and PPIB; however, it also increased the phosphorylation of PERK, and upregulated the expression of PERK, BIP, CHOP and cleaved caspase-3. The results indicated that CsA could induce pancreatic β cell dysfunction and the potential mechanism underlying this phenomenon may be PPIB-associated proinsulin misfolding, which in turn induces ER stress in β cells.

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“…Citterio et al have shown that AUC monitoring would be a better predictor of clinical outcomes in HSCT, while other trials did not find an association between AUC and clinical outcomes . At present, numerous monitoring methods have been proposed in the literature, but unfortunately, there is no consensus for the best practice in the HSCT field …”

Section: Discussionmentioning

confidence: 99%

Impact of cyclosporine‐A concentration in T‐cell replete haploidentical allogeneic stem cell transplantation

Yang

Sun

et al. 2018

Clinical Transplantation

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This paper aims to study whether cyclosporine-A (CSA) levels have an impact on the clinical outcome of patients with T-cell replete haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT). We analyzed 140 consecutive patients who had been given T-cell replete haploidentical allo-HSCT in our institute to assess the effect of CSA concentration in the early stages of allo-HSCT on clinical outcomes, such as hematopoietic recovery, acute graft vs host disease (aGVHD), infection, disease-free survival (DFS), and overall survival (OS). The median concentrations of CSA in the blood in the 1st, 2nd, 3rd, and 4th week after allo-HSCT were 218, 235, 263, and 270 ng/mL, respectively. Additionally, 46%, 40%, 27%, and 18% of the patients had CSA blood levels below 200 ng/mL during those weeks. In total, 39 patients developed aGVHD (grade II-IV), for a cumulative incidence of 27.8%, at a median of 32 days. Patients having a low CSA concentration (below 200 ng/mL) in the 3rd week had a higher cumulative incidence of grade II-IV aGVHD (P = .02). In addition, multivariate logistic regression analysis showed that low CSA concentration (below 200 ng/mL) in the 3rd week was an independent risk factor of grade II-IV aGVHD (P = .02; odds ratio = 2.66; 95% CI, 1.15-6.17). However, CSA levels during the first 4 weeks did not have a significant impact on the patients' hematopoietic recovery, infection, DFS, and OS. Our data indicated that adequate management of CSA levels during the peri-engraftment period might improve clinical outcomes for those with T-cell replete haploidentical allo-HSCT.

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Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

Cited by 16 publications

References 182 publications

Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats

Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats

Inhibition of peptidyl‑prolyl cis‑trans isomerase B mediates cyclosporin A‑induced apoptosis of islet β cells

Impact of cyclosporine‐A concentration in T‐cell replete haploidentical allogeneic stem cell transplantation

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