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

Abstract

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.

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

“…In dogs, as in humans, CsA absorption administered as vegetable oil formulation is highly dependent on biliary excretion (Venkataramanan et al. , 1986; Takaya et al. , 1989) as well as pancreatic secretion (White et al.…”

Influence of Partial Hepatectomy on Theophylline Pharmacokinetics in Rats

“…Notwithstanding the lowered E h for HG, there were no significant differences between both groups (p ) 0.42) on the F value (CG, 0.962 ( 0.008; HG, 0.970 ( 0.004), which can be due to the low theophylline CL int and its moderate plasma protein binding. These findings suggest that there will be no modifications in theophylline oral bioavailability after hepatectomy, although Takaya et al 7 have found a lower bioavailability for cyclosporin, but that has been explained as a consequence of a lower absorbed dose fraction. These results should be considered when planning dosages to be given in humans in the posthepatectomy hepatic regeneration phase.…”

“…Likewise, the plasma content decreased in HG, which has also been observed by Hall et al 5 Transaminase levels were raised significantly (p < 0.05) after hepatectomy, a fact also observed by Tanaka and Tokiwa. 6 As in the experiments of Takaya et al, 7 an increase in total and direct bilirubin levels 12 h after hepatectomy has been detected. Nevertheless, in our study the differences have not been statistically significant (p > 0.05), probably as a consequence of the big variability found for these parameters values.…”

“…[1][2][3][4] Partial hepatectomy induces changes in hepatocyte function and in plasma protein nature and quantity, as well as in bile flow, among other changes. [5][6][7] In view of the fact that the liver is an important site of drug metabolism and elimination, these changes can have an effect on the distribution, elimination, and even absorption of drugs, especially on those which are mainly eliminated through the liver. 8 In these cases a dosage adjustment may be necessary depending on the liver elimination capacity.…”

“…There are a few literature reports about the influence of hepatectomy on drug disposition. [5][6][7][8][9] To analyze the influence of hepatic alterations on posology, drugs are classified according their hepatic extraction coefficient (E h ) in three groups: low (E h < 0.3), intermediate (0.3 < E h < 0.7), and high (E h > 0.7) hepatic clearance drugs. In this study theophylline has been chosen as a model drug to analyze the influence of partial hepatectomy on the disposition of low hepatic clearance drugs.…”