Pharmacokinetics of Dirithromycin in Patients with Mild or Moderate Cirrhosis

ABSTRACT The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh’s & Child’s classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 ± 0.22 mg/liter in volunteers and 0.48 ± 0.21 and 0.52 ± 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t 1/2β) was 23.3 ± 7.6 h in healthy subjects and 35.2 ± 11.8 h and 39.5 ± 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t 1/2β were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t 1/2β or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.

Evaluation of the Behavior of Carcinoembryonic Antigen in Cirrhotic Patients

Benign liver diseases are a cause of increased serum levels of CEA. We studied the behavior of CEA in 86 patients with liver cirrhosis who underwent extensive clinical and laboratory evaluation. We found abnormal CEA levels in 38.4% of the patients (28.6% Child's grade A, 40.6% Child's B, and 42.4% Child's C) with a mean of 4.75 ng/ml. Significant differences were found between patients and controls. There was a trend towards higher levels of CEA in more severe cirrhosis according to Child's classification, although this was not significant. We found significant correlations between CEA and some liver tests, including glycocholic acid (r = 0.264., p = 0.012), a marker of severity in liver diseases. The increase of CEA in these patients is probably due to alterations in its metabolic processing caused by hepatocellular dysfunction. Moderate elevations of serum CEA can be expected in cirrhotic patients independently of malignancy.

Pattern and concentration of free and acetylated polyamines in urine of cirrhotic patients

The pattern and concentration of urinary, free, monoacetylated and total polyamines were determined in 31 cirrhotic patients, divided into three classes according to Child's classification, and in 28 healthy subjects. Cirrhotic patients had increased levels of free, monoacetylated and total polyamines. They also showed a significant increase in N1-acetylspermidine to N8-acetylspermidine molar ratio. Urinary polyamine excretion was not related to the severity of liver disease nor to the values of laboratory liver function tests. Furthermore, polyamine excretion was not significantly different in cirrhotics with or without diabetes or IGT, while plasma insulin and glucagon levels were increased in all cirrhotic patients. The results suggest that enhanced polyamine biosynthesis and catabolism, particularly N1-acetylation, occur in cirrhotic patients, probably due to hepatic regeneration and/or increased levels of insulin and glucagon.

Pre-Operative Assessment for Biliary Tract Surgery

The pre-operative approach to the patient with prolonged jaundice due to a long-standing obstruction of the bile duct is, we find, very similar to that of the patient with hepatic parenchymal disease who requires surgery for the treatment of portal hypertension. Complex and sophisticated tests of liver function are not required and a reasonable assessment of the patient's ability to withstand operation may be made by estimating the serum ammonia and bilirubin and the plasma glucose and albumin. Particularly useful in this assessment is the Child's classification (Child, 1964). This is based on 3 clinical and 2 laboratory tests. On this basis the patient may be assigned to 1 of 3 groups. Patients who belong to Child's group A have good hepatic reserve and are similar to individuals who have been deprived of no more than 30 per cent of their liver function. Patients of Child's group C, on the other hand, are similar to patients who have lost 90 to 95 per cent of liver function and operation in them carries a considerable risk. Moreover, because of their basic disease, the liver may have no regenerative powers and further improvement in liver function cannot be expected. These patients are hardly ever operable, although certain supportive measures may improve their general status and they may eventually be operated upon but considerable risks must be recognised. In an intermediate position are the patients who belong to group B of the Child's classification. These patients have evidence of hepatic dysfunction and require the energetic and detailed preparation described below.