Cyclosporine Disposition in the Dog

Buice, Robert G.; Gurley, Bill J.; Stentz, Frankie B.; Sidhu, Paramjeet; Mcclellan, Tamela; Williams, James W.

doi:10.1097/00007890-198511000-00003

Cited by 10 publications

(11 citation statements)

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“…Earlier pharmacokinetic studies demonstrate also a limited individual variability of the clearance and the oral bioavailability. Clearance has been consistently found to be in the range of 3.66–7.10 mL/min/kg (Buice et al. , 1986; Gridelli et al.…”

Section: Discussionmentioning

confidence: 99%

“…, 1989; Myre et al. , 1991) and oral bioavailability of the vegetable oil formulation close to 25% (range 20–27%) (Buice et al. , 1986; Gridelli et al.…”

Section: Discussionmentioning

confidence: 99%

“…CsA pharmacokinetics are very similar in dogs and man. The absolute bioavailability of CsA in dogs is in the range of 20–27% following the administration of a vegetable oil based formulation (Buice et al. , 1986; Gridelli et al.…”

Section: Introductionmentioning

confidence: 99%

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Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs

Steffan¹,

Strehlau²,

Maurer³

et al. 2004

Vet Pharm & Therapeutics

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A series of experiments was conducted to study cyclosporin A (CsA) pharmacokinetics in dogs and the factors influencing variability of blood concentrations. In a first study, influence of feeding on drug absorption and blood profile was evaluated. Administration of CsA as micro-emulsion (ME) formulation with food decreased the bioavailability by 22% and increased the individual variability of drug absorption. In a second study, pharmacokinetic profiles from laboratory fasted beagle dogs receiving orally CsA ME formulation were analyzed. CsA was measured in blood samples by high-performance liquid chromatography (HPLC, 34 profiles) and fluorescent polarization immunoassay (FPIA, 16 profiles). A two-compartment model with first-order absorption was used to calculate the pharmacokinetic parameters. Using FPIA, blood concentrations were 1.5 to 1.7 times higher than when using HPLC, but elimination half-life and MRT were similar. The coefficient of variation of key pharmacokinetic parameters ranged from 27 to 34% following HPLC assay. The same range of variation was obtained after FPIA assay. In a third study, in a clinical trial evaluating CsA for the treatment of canine atopic dermatitis, a single blood sample was collected in dogs which had received CsA for 28 days. No significant correlation was found between clinical improvement and CsA blood concentrations. Considering the large margin of safety of CsA in dogs, the limited inter-individual variability and the lack of correlation between blood concentrations and clinical response, routine monitoring of blood CsA does not appear necessary in dogs with atopic dermatitis.

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Section: Discussionmentioning

confidence: 99%

“…, 1989; Myre et al. , 1991) and oral bioavailability of the vegetable oil formulation close to 25% (range 20–27%) (Buice et al. , 1986; Gridelli et al.…”

Section: Discussionmentioning

confidence: 99%

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Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs

Steffan¹,

Strehlau²,

Maurer³

et al. 2004

Vet Pharm & Therapeutics

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“…The purpose of this study was to examine the CsA-KC interaction in the dog; a model that has been used extensively in CsA-dosing studies [17][18][19][20][21]. Specifically, we evaluated the effect of incremental increases in the dose of concomitant KC on CsA total body clearance [C1(T)] and CsA parent/parent + metabolite ratios in the blood under steadystate dosing conditions.…”

Section: Introductionmentioning

confidence: 99%

Critical Ketoconazole Dosage Range for Ciclosporin Clearance Inhibition in the Dog

Sa¹,

Tj²,

Vr³

et al. 1991

Pharmacology

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Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p > 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p > 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p < 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p > 0.05). We conclude from these new observations that the KC-induced decrease in CsA C1(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5–10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.

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“…There is also the possibility that CsA might be extensively distributed into peripheral body regions in the case of hepatic injuries, and the influence of the entero-hepatic circulation of CsA should also be considered. 18 The data in this experiment demonstrates that liver impairment significantly influences the pharmacokinetics of CsA, not only by changes in the intestinal absorption but also by changes in hepatic metabolism. Safe and effective therapy will require an improved understanding of how CsA pharmacokinetics very with the degree and cause of hepatic dysfunction.…”

Section: Discussionmentioning

confidence: 70%

The influence of liver dysfunction on cyclosporine pharmacokinetics —A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs—

Takaya

Iwatsuki

Noguchi

et al. 1989

The Japanese Journal of Surgery

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The influence of experimentally induced hepatic dysfunction on the pharmacokinetics of Cyclosporine A (CsA) was determined in dogs. The pharmacokinetics of oral (PO) and intravenous (IV) CsA were studied before and after 70 per cent hepatectomy or complete bile duct ligation (CBDL). Changes in liver function were monitored by serial measurements of serum bilirubin, and by the maximum removal rate (Rmax) and plasma disappearance rate (ICG-K) of indocyanine green (ICG). Concentrations of CsA in whole blood were measured by HPLC. Seventy per cent hepatectomy caused significant liver dysfunction: the ICG-Rmax decreased by 47.7 ± 7.1 per cent (mean ± SD) and the ICG-K decreased by 61.3 ± 9.7 per cent during the first week after hepatectomy. At the same time, the systemic clearance (CLs) of IV-CsA decreased by 43.9 ± 8.2 per cent, the area under the concentration curve (AUC) of IV-CsA increased by 35.4 ± 20.8 per cent and the bioavailability of CsA decreased by 26.4 ± 14.8 per cent. CBDL also induced significant liver dysfunction: the ICG-Rmax decreased by 39.1 ± 12.8 per cent and the ICG-K decreased by 65.6 ± 3.6 per cent in the second week after the operation. During the same period, the AUC of PO-CsA decreased by 69.9 ± 10.7 per cent and the bioavailability of CsA also decreased markedly by 73.9 ± 15.6 per cent. These data indicate that hepatic impairment significantly influences the pharmacokinetics of CsA, not only by the changes in intestinal absorption, but also by those in hepatic metabolism. Dose adjustment is therefore necessary in the presence of hepatic dysfunction in order to maintain an adequate blood concentration of CsA without causing side effects.

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Cyclosporine Disposition in the Dog

Cited by 10 publications

References 0 publications

Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs

Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs

Critical Ketoconazole Dosage Range for Ciclosporin Clearance Inhibition in the Dog

The influence of liver dysfunction on cyclosporine pharmacokinetics —A comparison between 70 per cent hepatectomy and complete bile duct ligation in dogs—

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