Clinical observations indicate an increased number of post-operative complications and deaths in jaundiced patients. The patient may require some simultaneous treatment of concomitant ailments, among which
cardiovascular diseases occur rather frequently. Some of the drugs administered then, like
digoxin, are, in spite of being predominantly eliminated via the kidneys, metabolized in the liver, secreted into the bile or participating in the enterohepatic circulation. The changed pharmacokinetics of such drugs, in the case of
mechanical jaundice, may be due to an altered liver status which can affect the function of the kidneys. The aim of the study was to evaluate the pharmacokinetics of
digoxin administered both intravenously and into the stomach, in the state of mechanical,
extrahepatic cholestasis. The study was carried out on male rabbits, divided randomly into four groups: the first two (experimental and control) were administered
digoxin intragastrically and the next two groups (experimental and control)-intravenously (Tab. 1). The animals of the experimental groups had the bile ducts ligated, whereas the controls were
sham-operated on.
Digoxin was given to all the animals 4 days before the operation and 6 days after the surgery, in a dose of 0.02 mg/kg. Blood samples were collected ten times for 24 hours after the
drug administration.
Digoxin concentrations were determined by FPIA method, and pharmacokinetic parameters were calculated by the two compartment open model for intragastric
drug administration, and by the noncompartmental analysis for intravenous route. The levels of serum total
bilirubin,
creatinine,
urea,
glucose,
albumin and activities of
alanine,
aspartate aminotransferases and
alkaline phosphatase were estimated in all of the animals. The rabbits were sacrificed at the end of the study i.e. on the 7th day after the operation. The kidneys and the livers were weighed and examined macro- and microscopically. The laboratory tests as well as the anatomopathological investigations showed the symptoms of
cholestasis and the
hepatorenal syndrome (Tab. 2, 3). The blood serum concentrations of
digoxin, both after intragastric and
intravenous administration, were statistically higher during the whole observation period in the animals with obstructive
cholestasis versus the controls (Tab. 4, 6). There were no significant alterations of
digoxin parameters in the animals of the control groups, measured prior to and after the surgery. In the jaundiced animals, however, most of the pharmacokinetic parameters were markedly changed as compared with the preoperative values. In the rabbits which were given
digoxin intragastrically, an increase in area under the plasma concentration-time curve (AUC) and in the peak concentration of the
drug (Cmax) was noted (Tab. 5). Besides, the prolongation of mean residence time (MRT) and decrease in total body clearance (Cl) as well as apparent volume of distribution (Vz), were observed, as compared to the
sham-operated controls. After the
intravenous administration the following changes took place (Tab. 7): an increase in AUC, the prolongation of elimination half-life (t1/2 lambda z) and decrease in the total body clearance. All the above differences were statistically significant. Thus,
digoxin, a
drug predominantly eliminated via the kidney undergoes an impaired elimination in obstructive
cholestasis. Basing on the results of the present study, the following statements could be expressed: (1) experimental, extrahepatic
jaundice alters the pharmacokinetics of
digoxin given intragastrically as well as intravenously; (2) the administration of therapeutic dose of
digoxin in the state of
mechanical jaundice may lead to its overdose; (3) obstruction of the common bile duct should indicate the necessity of monitoring the serum concentration of
digoxin; (4)
extrahepatic cholestasis may induce
hepatorenal syndrome.