[The effect of experimental extrahepatic cholestasis on absorption, distribution and elimination of digoxin].
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.
Wójcicki
M
M
Samodzielnej Pracowni Farmakokinetyki i Terapii Monitorowanej Katedry Farmakologii i Toksykologii Pomorskiej Akademii Medycznej w Szczecinie.
D000042:Absorption; D000818:Animals; D019540:Area Under Curve; D001651:Cholestasis, Extrahepatic / Q000503:physiopathology*; D000075202:Contraindications; D004077:Digoxin / Q000493:pharmacokinetics*; D006207:Half-Life; D007441:Intubation, Gastrointestinal; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D014018:Tissue Distribution
D004077:Digoxin