Drugs in liver disease and during albumin dialysis -MARS

In liver diseases the pharmacokinetics and pharmacodynamics of drugs may be changed to a different degree. At present, there is no satisfactory test for the quantitative determination of metabolic liver function. Child-Pugh scoring is a poor predictor of drug-metabolising capacity. In patients with liver disease the grade of reduction of the metabolic capacity (dependent on hepatic blood flow and enzyme activity) and of plasma protein binding rate as well as the influence of extrahepatic elimination is difficult to foresee. Precise determination of drug dosage in liver insufficiency requires information on physicochemical and pharmacokinetic properties of the drugs, their particular metabolic pathway (e. g. enzymes involved), the effect of liver disease on the different CYP450 isoenzymes, the possibility of multiple interactions in addition to the changes in plasma protein binding and pharmacodynamics. After repeated administration, the risk of drug accumulation increases while the extrahepatic elimination is impaired (e. g. hepatorenal syndrome). In chronic liver disease with cirrhosis, dosage reduction is generally recommended regardless of the route of drug elimination, since most drugs are eliminated by both, hepatic and renal.

Our observations suggest that the drug accumulation in liver cirrhosis can occur also with unmetabolized drugs with low protein binding such as levofloxacin and ciprofloxacin (half-life time increase 14 h vs. 7 h for levofloxacin and 35 h vs. 4 h for ciprofloxacin; reduction of total clearance, 70 vs. 180 ml/min and 35 vs. 70 ml/min, respectively).

The Molecular Adsorbent Recirculating System (MARS) is especially designed for the removal of albumin bound toxins in liver failure. The aim of our study was to investigate the extracorporeal elimination of different drugs during MARS-treatment and the necessity of modification of their dosage. Therefore, in an in vitro model was performed and compared with conventional in-vitro dialysis (CVVHD). The concentrations were measured in plasma and dialysate during the procedure. The elimination of drugs with a different albumin binding rates (highly albumin bound antibiotics: ceftriaxone and teicoplanin, slightly bound: ceftazidime and levofloxacin) were compared. It was shown that the elimination of the high protein bound drugs is significantly higher with albumin dialysis (MARS) than in conventional albumin-free continuous dialysis (CVVHD). In the conventional CVVHD, the concentration of ceftriaxone (Figure [1]) decreased during six hours from 117.3 to 94.4 (20 %) and in MARS from 119.2 to 34.9 mg/L (71 %). Reduction of teicoplanin (Figure [2]) was in CVVHD from 51.3 to 22.2 (58 %) and in MARS from 47.1 to 4.9 mg/L (90 %). Elimination of teicoplanin is probably also due to adsorption to the membrane in CVVHD and MARS. Both, ceftazidime (low volume of distribution) and levofloxacin (higher volume of distribution) have no specific affinity to serum albumin. The high clearance of these drugs in the MARS procedure is clearly linked to the higher dialysate flow rate in MARS (150 versus 15 mL/min in CVVHD). Ceftazidime concentration (Figure [3]) was reduced from 114.0 to 1.8 (98.4 %) in CVVHD and 87.3 to 0.13 mg/L (99.8 %) in MARS. In the CVVHD, the concentration of levofloxacin (Figure [4]) decreased during six hours from 7.7 to 0.05 (99.3 %) and in MARS from 7.02 to 0.05 mg/L (99.3 %). The removal of ceftazdime and levofloxacin was in MARS faster than in CVVHD (t_1/2-MARS<<t_1/2-CVVHD).

Figure 1 Ceftriaxone (high albumin bound, low volume of distribution)

Figure 2 Teicoplanin (high albumin bound, high volume of distribution)

Figure 3 Ceftazidime (low albumin bound, low volume of distribution)

Figure 4 Levofloxacin (low albumin bound, high volume of distribution)

We conclude, the use of drugs in patients with liver failure has to be constantly monitored for adverse drug reactions. Drug treatment during MARS should follow the rules of intermittent dialysis: dosage after treatment. For continuous MARS treatment drugs with a narrow therapeutic range may require continuous infusion and drug monitoring, if possible. According to our first experiences with liver disease patients during MARS treatment no dosage adjustment for low albumin bound drugs is required.

We thank Ms. K. Krösche and Ms. G. Hahn for her skilful technical assistance.

This work was supported by the German Ministry for Education and Research (grant 01EC9404).

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