Hepatic and renal blood flow responses to a clinical dose of intravenous cyclosporine in the pig

doi:10.1016/0162-3109(94)90024-8

Immunopharmacology

Volume 28, Issue 2, September–October 1994, Pages 87-94

Immunopharmacology

https://doi.org/10.1016/0162-3109(94)90024-8 Get rights and content

Abstract

The immunosuppressant Cyclosporine A (CsA) is considered to induce nephrotoxicity in part by causing vasoconstriction of the glomerular afferent arterioles. Although CsA is widely used in hepatic transplantation, little is known concerning its effects on hepatic blood flow. We used ultrasonic flow probes in an anesthetized swine model to measure the effects of a single 60 min infusion of a clinically comparable dose of CsA (5 mg/kg per h) on hepatic, renal, and supraceliac descending aortic blood flows (n = 7 swine). To account for any changes in systemic output or systemic vascular resistance during the 60 min CsA infusion that may non-specifically affect hepatic and renal blood flows, the total hepatic (portal vein plus hepatic artery) and renal blood flows were reported relative to the supraceliac descending aortic blood flow (termed ‘fractional’ total hepatic and renal blood flows). The fractional total hepatic blood flow decreased significantly (p < 0.05) by 40 min of CsA infusion vs baseline, and continued to decrease throughout the infusion (baseline = 0.38 ± 0.03 units vs 0.28 ± 0.05 units by 60 min of CsA infusion). During the recovery period, the fractional total hepatic blood flow increased to a value which was not different from baseline (recovery = 0.38 ± 0.03 units). Fractional right renal artery blood flow did not change significantly from baseline at any time during the CsA infusion or during the recovery period. We conclude that a single, clinically comparable dose of CsA results in a significant decrease in total hepatic blood flow, and that this decrease is greater than that seen in renal blood flow.

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Cited by (8)

Cyclosporine A-induced acute hepatotoxicity in guinea pigs is associated with endothelin-mediated decrease in local hepatic blood flow
2011, Life Sciences
Citation Excerpt :
Most of the studies on this field have examined the CsA- or ET-1-induced changes in rat isolated hepatocyte perfusion or on biochemical measures. The change in the hepatic artery flow in response to CsA administration has also been studied (Andreoni et al. 1994). The present in vivo study aimed to examine the acute effect of CsA on LHBF which is a direct indicator of local liver perfusion, and to correlate the hemodynamic changes with biochemical and histopathological measures in guinea pigs.
To bring further insight into the mechanism of cyclosporine A (CsA)-induced hepatotoxicity, the acute effect of CsA on local hepatic blood flow (LHBF) and its association with systemic hemodynamics, histopathological and biochemical indicators of liver toxicity were studied in guinea pigs in vivo. The association of endothelin (ET) and/or Cremophor-EL (C-EL, vehicle in parenteral CsA preparation) with CsA effects was also investigated.
Animals were assigned into five groups; control, CsA, C-EL, Bosentan (non-selective ET receptor antagonist) + CsA, and BQ-123 (ET_A receptor antagonist) + CsA. CsA was infused intravenously (i.v.) at 20 and 10 mg/kg doses by 15 min interval. Antagonists were administered 15 min before CsA infusion. LHBF and mean arterial blood pressure (MAP) changes were simultaneously recorded. Blood and liver samples were collected for biochemical and histopathological examinations.
CsA, but not C-EL, decreased LHBF by 53.3% at the end of 30 min. Although being non-significant, CsA slightly increased MAP suggesting that, CsA-induced acute decrease in LHBF was likely independent of MAP changes. Bosentan (5 mg/kg, i.v.) and BQ-123 (1 mg/kg, i.v.) pre-treatments prevented the CsA-induced decrease in LHBF suggesting that CsA decreases LHBF through an ET-related mechanism. Additionally, CsA, but not its vehicle C-EL, caused marked acute pathological changes in the liver morphology.
CsA-induced findings of acute hepatotoxicity were prevented by bosentan and BQ-123 pre-treatments. Thus, CsA seems to exert acute hepatotoxic effect through ET-related mechanisms.
Pharmacokinetic characterization of a pig model of ciclosporin A nephrotoxicity following intravenous administration
2007, Pharmacological Research
Recently, we investigated pharmacokinetics and acute nephrotoxicity of oral ciclosporin A (CsA) in pigs. We found that pigs require higher oral CsA doses to obtain comparable area under the concentration versus time curve (AUC) levels to renal transplant patients. The purpose of this study was to examine pharmacokinetics and possible acute renal effects of intravenous CsA in order to further characterize the pig as a model of CsA nephrotoxicity.
Twenty-eight pigs were randomized into four groups: control and three groups subjected to a single CsA infusion at 3, 6, or 9 mg kg⁻¹. Blood samples for determination of whole blood CsA concentrations were collected over 7 h under general anaesthesia. At 0, 2, and 5 h, we measured blood pressure, serum creatinine, and haemoglobin, as well as renal blood flow (RBF), relative glomerular filtration rate (rGFR), and kidney volume using magnetic resonance imaging.
CsA distribution exhibited two-compartmental behaviour. Compared to renal transplant patients, pigs had approximately the same total clearance of CsA (mean 0.31–0.34 l h⁻¹ kg⁻¹), which yields comparable AUC after equivalent dosage in both species. However, the volume of distribution at steady state (mean 1.9–3.0 l kg⁻¹) was lower in pigs. RBF remained stable in all groups, whereas rGFR decreased in all groups reaching statistical significance in the controls.
Pigs require approximately the same intravenous CsA doses to obtain comparable total AUC to renal transplant patients. Single CsA infusion up to 9 mg kg⁻¹ for 1 h has no deteriorating effect on renal haemodynamics and function.
The pharmacokinetics and acute renal effects of oral microemulsion ciclosporin A in normal pigs
2006, International Immunopharmacology
Citation Excerpt :
In the CsA 30 mg group RBF was expected to be higher because of the weight gain and increase in blood flow [17], and our results indicate therefore also an acute reduction in this functional parameter by CsA 30 mg/kg, whereas no change in RBF was seen with CsA 15 mg/kg. RBF response to CsA in pigs has previously been investigated by Calvert and Terris [18] and Andreoni et al. [19]. Calvert et al. were unable to demonstrate any significant changes in RBF in response to CsA.
The use of ciclosporin A (CsA) is limited by nephrotoxicity. Anatomic and physiologic similarities to humans make the pig a potential important animal model for research in effects and adverse events of CsA. In a long-term study CsA 10 mg/kg/day for 6 months did not cause deterioration in renal histology or function in pigs. For ideal CsA dosage in future long-term studies of nephrotoxicity we performed this study to describe pharmacokinetics and acute effects on renal function of CsA in normal pigs.
Three groups of 5 piglets comprised the material, a control group and 2 groups receiving 5 days treatment with CsA (Neoral) 15 or 30 mg/kg/day, respectively. CsA whole blood concentration (B-CsA) (hourly), renal blood flow, glomerular filtration rate (GFR) and serum creatinine were measured. The area under the curve from time 0 to 12 h was calculated using the Trapezoidal Rule. Pharmacokinetic calculations were performed using the KINFIT non-linear curve fitting module.
B-CsA reached peak in median at 0.90 and 0.96 h (633 and 914 ng/ml) in the 15 and 30 mg/kg/day groups, respectively, and median AUC was 5055 and 6275 h ng/ml, respectively. Trough levels were 338 and 475 ng/ml. The distribution of CsA followed a 2-compartment model. Serum creatinine was 111 (control), 112 (15 mg/kg/day) and significantly increased to 168 ìmol/l in 30 mg/kg/day group, which also had a reduction in GFR compared to the other 2 groups.
CsA causes acute nephrotoxicity in piglets. The distribution follows a 2-compartment model similar to humans, but higher doses are necessary in pigs.
Plasma concentration of hGH and anti-hGH antibodies after subcutaneous administration of hGH for 3 weeks to immunosuppressed pigs
1999, Journal of Pharmacological and Toxicological Methods
Objective: The objective of the present study was to evaluate the dosing regimen of immunosuppressants necessary to avoid the formation of anti-hGH antibodies in a pig model.
Animals: Sixteen pigs were divided into four groups.
Procedure: Three different immunosuppressive treatments were tested (group 1: Control (no treatment); group 2: 10 mg; group 3: 20 mg; and group 4: 40 mg cyclosporine; combined with 2 mg azatioprine and 2 mg prednisolone p.o./kg/day). The treatments were given from days −7 to 22.
All groups were dosed subcutaneously (s.c.) with 0.5 mg hGH/kg once daily from days 1 to 22. On the first and the last days of dosing blood samples were collected to describe the hGH concentration versus time profile. Before dosing and on days 5, 10, and 15 blood samples were collected for measuring hGH antibody formation.
Results: A dose-dependent decrease in white blood cell counts was observed in all immunosuppressive-treated groups. Groups 1 and 2 produced antibodies against hGH during the 22 days of dosing while the formation of antibodies was suppressed in groups 3 and 4. In the control group and group 2 the pharmacokinetic parameters of hGH were influenced by the formation of anti-hGH antibodies. In groups 3 and 4, the pharmacokinetic parameters were comparable on the first and the last day of dosing.
Conclusion: The formation of anti-hGH antibodies influenced the pharmacokinetics of hGH in pigs, but it could be prevented by immunosuppressive therapy. From the present experiment, a dose of 20 mg cyclosporine, 2 mg azatioprine, and 2 mg prednisolone p.o./kg/day was able to prevent the pigs from producing antibodies without having severe adverse effects. This model may by useful in future experiments using sustained release formulations of hGH, and possibly for other compounds that may induce antibody production in pigs.
Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series
2013, Clinical and Experimental Rheumatology
Post-conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model
2010, Acta Anaesthesiologica Scandinavica

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Hepatic and renal blood flow responses to a clinical dose of intravenous cyclosporine in the pig

Abstract

Am J Med

Lancet

Lancet

Pharmacol Rev

J Am Soc Nephrol

Long-term effects of cyclosporine on renal function in organ transplant recipients

J Lab Clin Med

Active hepatic capacitance responses to neural and humoral stimuli in dogs

Am J Physiol

The hemodynamic effects of cremophor-EL

Transplantation

Effect of nifedipine on cyclosporin A-induced, urinary endothelin excretion and renal endothelin receptor number

Eur J Pharmacol

Cyclosporine-induced synthesis of endothelin by cultured human endothelial cells

J Clin Invest

Dose-dependent effect of cyclosporin on renal arterial resistance in dogs

Am J Physiol

Comparison of the effects of cyclosporine and its metabolites on the release of prostacyclin and endothelin from mesangial cells

Transplantation

Effects of stimulation of the hepatic nerves and of adrenaline upon the circulation of the portal venous blood within the liver

J Physiol

Increased endothelin level after cyclosporine therapy (letter to the editor)

Ann Int Med