Pharmacokinetic parameters of antipyrine in dog after hepatectomy

Abstract

Pharmacokinetic studies with antipyrine were carried out on beagle dogs to determine the consequence of hepatectomy on hepatic drug metabolizing capacity, the rate of hepatic regeneration, and the possible beneficial effect of hepatocellular transplantation. The drug (250 mg) was administered by short IV infusion in three groups of dogs (first group, 65% hepatectomy; second group, 65% hepatectomy with hepatocyte transplantation; third group 80% hepatectomy). Pharmacokinetic parameters of antipyrine were evaluated before surgery and within 10 d after surgery. Blood samples were taken at frequent intervals after drug administration and antipyrine was assayed in plasma by a specific HPLC method with UV detection. Before surgery, the mean elimination half-life was about 1.1 h and total clearance averaged 6 L h-1. In dogs with 65% hepatectomy, no statistical differences in pharmacokinetic parameters of antipyrine appeared before or after surgery. When 65% hepatectomy was associated with hepatocyte transplantation, a significant increase in elimination half-life and a significant decrease in total clearance were observed. The same statistical differences in the pharmacokinetic parameters were observed in the group with 80% hepatectomy. Transplantation of isolated hepatocytes into the spleen did not correct hepatocellular insufficiency. In this study, numerous laboratory tests were performed. A significant correlation was found between serum albumin, cholesterol, factor V, ALAT, total bilirubin, and ratio of amino acids and the pharmacokinetic parameters of antipyrine.

Morphological Regeneration and Hepatic Functional Mass after Right Hemihepatectomy

“…In rat two-third partial hepatectomy model, the functional restoration of the liver is retarded compared to morphologic restoration, and intrinsic clearance per unit liver volume is only approximately 60% of the preoperative value even on POD 20, partly because hepatic cytochrome P450 decreased with a decrease in liver weight in this model [27, 28]. While in a dog 65% hepatectomy model, no significant differences in pharmacokinetic parameters of antipyrine were seen between before and after hepatectomy [29]. These suggest that different species may show different responses in antipyrine metabolism by P450 enzyme during liver regeneration after hepatic resection, and we should take great care to interpret the results from animal models, especially in terms of liver regeneration after hepatectomy.…”

Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver

“…It is necessary to study how to use them carefully, including their effect on hepatic regeneration and function after hepatic injury. There are reports on the pharmacokinetics of tacrolimus, mycophenolic acids [25] and antipyrine [26] on various conditions of liver damage. In both cases, the pharmacokinetics were altered.…”

Influence of Partial Hepatectomy on Theophylline Pharmacokinetics in Rats

“…Among these there are reports about three extensively biotransformed drugs such as 4′-epidoxorubicin, 5 cyclosporine, 7 and antipyrine, 8 besides others such as cisplatin, 9 and the recombinant human granulocyte colony stimulating factor. 6 These works show that hepatectomy, in general, causes an increase in AUC, whereas the distribution volume and C 0 values may increase, decrease, or even remain constant.…”

“…[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. An increase in the knowledge of the disposition characteristics of drugs administered during the posthepatectomy period will permit optimization of the dosage regimen of drugs and increase their therapeutic efficacy.…”

“…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.…”