Coadministration Of Cyclosporin A Research Articles

Carbon disulfide induces rat testicular injury via mitochondrial apoptotic pathway

Carbon disulfide (CS2), one of the most important volatile organic chemicals, was shown to have serious impairment to male reproductive system. But the underline mechanism is still unclear. In the present study, we aim to investigate the male germ cell apoptosis induced by CS2 exposure alone and by co-administration with cyclosporin A (CsA), which is the inhibitor of membrane permeability transition pore (MPTP). It was shown that CS2 exposure impaired ultrastructure of germ cells, increased the numbers of apoptotic germ cells, accumulated intracellular level of calcium, elevated ROS level, and increased activities of complexes of respiratory chain. Meanwhile, exposure to CS2 dramatically decreased the mitochondrial transmembrane potential (ΔΨm) and levels of ATP and MPTP opening. Exposure to CS2 can also cause a significantly dose-dependent increase in the expression levels of Bax, Cytc, Caspase-9, and Caspase-3, but decreased the expression level of Bcl-2. Moreover, co-administration of CsA with CS2 can reverse or alleviate the above apoptotic damage effects of CS2 on testicular germ cells. Taken together, our findings suggested that CS2 can cause damage to testicular germ cells via mitochondrial apoptotic pathway, and MPTP play a crucial role in this process.

The P-glycoprotein inhibitor cyclosporin A differentially influences behavioural and neurochemical responses to the antidepressant escitalopram

Recent studies have raised the possibility that P-glycoprotein (P-gp) inhibition may represent a putative augmentation strategy for treatment with certain antidepressants. Indeed, we have previously shown that administration of the P-gp inhibitor verapamil increased the brain distribution and behavioural effects of the antidepressant escitalopram. The aim of the current study was to investigate if similar effects occur with another P-gp inhibitor, cyclosporin A (CsA). CsA pre-treatment exacerbated the severity of behaviours in an escitalopram-induced mouse model of serotonin syndrome, a potentially life-threatening adverse drug reaction associated with serotonergic drugs. P-gp inhibition by CsA enhanced the brain distribution of escitalopram by 70–80%. Serotonin (5-HT) turnover in the prefrontal cortex was reduced by escitalopram, and this effect was augmented by CsA. However, CsA pre-treatment did not augment the effect of escitalopram in the tail suspension test (TST) of antidepressant-like activity. Microdialysis experiments revealed that pre-treatment with CsA failed to augment, but blunted, the increase in extracellular 5-HT in response to escitalopram administration. This blunting effect may contribute to the lack of augmentation in the TST. Taken together, the present studies demonstrate that co-administration of CsA and escitalopram produces differential effects depending on the behavioural and neurochemical assays employed. Thus, the results highlight the need for further studies involving more selective pharmacological tools to specifically evaluate the impact of P-gp inhibition on behavioural responses to antidepressants which are subject to efflux by P-gp.

P-glycoprotein-mediated efflux of phenobarbital at the blood-brain barrier evidence from transport experiments in vitro

The purpose of the present studies was to investigate characteristics of phenobarbital (PB) transport across the blood-brain barrier (BBB). Cultured rat brain microvascular endothelial cells (rBMECs) were used as an in vitro BBB model. Experiments were conducted to examine time-, concentration- and temperature-dependent elements of PB uptake, and the effect of tested agents on the steady-state uptake of PB. PB efflux from rBMECs and the polarised transport of PB were examined to evaluate whether P-glycoprotein (P-gp) was involved in the PB efflux transport across BBB. The results demonstrated that the uptake of PB by rBMECs was in a time-, concentration- and temperature-dependent manner. P-gp modulators, cyclosporin A (CsA), ketoconazole and metabolic inhibitor dinitrophenol, increased the PB steady-state uptake by more than 50% (p < 0.01), and decreased the PB efflux by more than 50% (p < 0.01). Similar results were observed in the uptake and efflux studies of rhodamine-123 by co-administration of CsA. Further results were obtained in the polarised transendothelial transport of PB in the apical to basolateral (A-B) and basolateral to apical (B-A) directions either with or without CsA. The result showed that transport of PB in the B-A direction was significantly greater than the transport in the A-B direction (p < 0.05), and the co-administration of 50microM CsA almost inhibited P-gp-involved efflux in the rBMECs. Overall, these findings suggest that P-gp may contribute to the efflux transport of PB across BBB.

DEMONSTRATION OF DOCOSAHEXAENOIC ACID AS A BIOAVAILABILITY ENHANCER FOR CYP3A SUBSTRATES: IN VITRO AND IN VIVO EVIDENCE USING CYCLOSPORIN IN RATS

To investigate the pharmacokinetic interaction between cyclosporin A (CsA) and docosahexaenoic acid (DHA) in vivo, 5 mg/kg CsA was orally or intravenously coadministered with DHA (50-200 microg/kg) to rats. The effect of DHA on CYP3A activity was determined using rat liver microsomes in vitro. Moreover, the effect of DHA on P-glycoprotein (P-gp) function was examined using cultured Caco-2 cells in vitro. After oral coadministration of CsA with 100 microg/kg and 200 microg/kg DHA, bioavailability (BA) was significantly increased, compared with control rats. In contrast, no pharmacokinetic interaction was observed when CsA was intravenously administered in rats dosed orally with DHA, suggesting that DHA did not affect hepatic metabolism. The formation of 6beta-hydroxytestosterone from testosterone in rat liver microsomes was competitively inhibited by DHA. The Km, Vmax, and Ki values were 25.5 microM, 2.45 nmol/min/mg protein, and 5.52 microM, respectively. Moreover, basal-to-apical transport of [3H]CsA in the Caco-2 cell monolayer was not affected by DHA but was decreased by valspodar (PSC 833), a P-gp inhibitor. Our finding is the first to indicate that DHA inhibits intestinal CYP3A both in vitro and in vivo, but not P-gp. It was thus demonstrated that DHA could be used as a BA enhancer for the drugs that are extensively metabolized by CYP3A in the gut.

Cyclosporin A aerosol improves the anticancer effect of paclitaxel aerosol in mice.

The objective of this study was to assess the effect of cyclosporin A liposome aerosol on the anticancer activity of paclitaxel (PTX) liposome aerosol against renal cell carcinoma (Renca) pulmonary metastases in mice. Cyclosporin A (CsA) was administered as a liposome aerosol for one-half hour before starting one-half hour treatment with PTX liposome aerosol (CsA/PTX), and in a second groups of animals cyclosporin A liposome aerosol was given before PTX for one-half hour and also later by mixing a second dose of cyclosporin A aerosol with PTX aerosol and extending the treatment period to one hour (CsA/PTX + CsA). In one experiment, PTX and CsA/PTX aerosols were significantly more effective compared to untreated controls against renal cell cancer as measured by lung weights and tumor surface areas. CsA/PTX was significantly better that PTX alone as measured by lung weights and tumor area. In a second experiment, tumor areas of PTX and CsA/PTX treated mice were significantly reduced compared to untreated controls and CsA/PTX treated mice had significantly smaller tumor areas than PTX treated mice. In contrast, tumor numbers were not significantly fewer than controls in either therapeutic group. In a third experiment, tumor numbers and tumor areas were significantly fewer in mice treated with CsA/PTX and CsA/PTX + CsA compared to untreated controls. Mice treated with CsA/PTX + CsA had significantly fewer tumors and less tumor area than mice receiving CsA/PTX. While PTX treated mice were not different than untreated controls with respect to tumor numbers or tumor volumes, PTX treated mice had significantly greater tumor numbers and tumor areas than CsA/PTX and CsA/PTX + CsA treated mice. Co-administration of CsA with PTX demonstrated significant dose dependent anticancer effects against renal cell pulmonary metastases in mice. Toxicity manifested by weight loss was associated with the highest dose of CsA.

Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A.

The distribution of domperidone (DOM), a peripheral dopamine D(2) receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D(2) antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D(1), D(2) and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D(1), D(2) and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D(1) and D(2) receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.

Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia.

To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); P < 0.01] and IDAOL [2896.60 (736.38) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l x h(-1) x m(-2) vs 139.65 (69.45) l x h(-1) x m(-2); NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) microg x h x l(-1) vs 315.44 (158.28) microg x h x l(-1); NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) microg x h x l(-1) vs 1028.49 (603.95) microg x h x l(-1); P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) microg x h x l(-1) vs 2896.60 (736.38) microg x h x l(-1); P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vdss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. The results show that CyA alone at a dose of 10 mg x kg(-1) daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered.

Toxic effect of concomitant administration of cyclosporin A and acyclovir on renal function and morphology in rats

The immunosuppressive agent cyclosporin A (CyA) and the antiviral drug acyclovir may cause renal functional impairment. CyA-induced immunosuppression increases the rate of viral infections. Therefore we were interested to determine whether short-term co-administration of CyA and acyclovir involves an increased nephrotoxic risk. Male Wistar rats were treated with CyA (20 mg/kg body wt., s.c., once daily for 8 days), acyclovir (15 mg/kg body wt., s.c., 3-times daily for the last 5 days) or a combination of CyA and acyclovir. Blood levels of CyA were determined after a single dose. Urine was monitored for volume, osmolality, total protein and N-acetyl-beta-D-glucosaminidase (beta-NAG). Concentrations of blood urea nitrogen (BUN) and plasma-creatinine were determined (day 9). Renal cortical slices were monitored for accumulation of weak organic acids (para-aminohippurate, PAH) and bases (tetra-ethylammonium, TEA) and for malondialdehyde (MDA) content. Renal histology was also examined. CyA induced a decrease in body and kidney weight, in urine osmolality and in the excretion of total protein. Plasma-creatinine and BUN as well as MDA content of renal tissues were increased by CyA. Acyclovir alone did not induce significant changes. In comparison to CyA values, urine volume and beta-NAG excretion were enhanced and TEA accumulation depressed by the concomitant administration of CyA and acyclovir. CyA- or acyclovir-treatment alone did not result in significant morphological changes. In the group co-administered CyA/acyclovir, the kidneys showed mild to moderate signs of tubulopathy. Short-term co-administration of CyA and acyclovir was concluded to have possibly increased nephrotoxic potential.

In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier

To evaluate the significance of P-glycoprotein (P-gp)-mediated active efflux on the blood-brain barrier (BBB) permeability of cyclosporin A (CsA) in vivo, we investigated the effects of ATP depletion in the brain and of a multidrug-resistant (MDR) reversing agent on the transport of CsA across the BBB. Using transient brain ischemia obtained by 4-vessel occlusion of vertebral and common carotid arteries in rats to deplete ATP content in the brain, the estimated permeability surface area product (PS) value of [ 3H]CsA was increased 2.7-fold compared with that in normal rats, whereas the PS value of [ 14C]sucrose was not altered. Additionally, when quinidine hydrochloride (QND) was infused into the brain through a microdialysis probe implanted in the rat hippocampus, the extravascular extraction of CsA was increased to approximately 2.5-fold of the control, whereas no difference in the extravascular extraction between control and normal rats having no implanted dialysis probe was observed. Furthermore, the efflux rate from brain to blood of CsA was decreased remarkably to 5% of control at steady-state by co-administration of CsA with QND directly into the brain through the dialysis probe. The ATP-dependent and QND-sensitive efflux of CsA from the brain strongly indicates that P-gp in the brain capillary endothelial cells functions as an efflux pump under the physiological state, and that P-gp-mediated efflux of CsA is a major mechanism of the restricted transfer from blood into the brain.