Influence of Partial Hepatectomy on Theophylline Pharmacokinetics in Rats

Abstract

The influence of partial hepatectomy on the pharmacokinetics of theophylline was determined in rats. The pharmacokinetics of intravenous theophylline was studied in unhepatectomized rats (control group: CG) and in hepatectomized rats (HG) 12 h after 70% hepatectomy. Liver function was monitored in both groups by measurements of total and direct bilirubin, transaminases GOT and GPT, and plasma protein. Seventy per cent hepatectomy caused significant liver dysfunction: transaminase levels (GOT and GPT) increased by 118 and 683%, respectively, and the total and direct bilirubin levels increased by 28.6 and 9.1%, respectively. At the same time, plasma concentrations of theophylline decreased significantly and half-life increased from 4.16 +/- 0.57 h (CG) to 7.08 +/- 0.69 h (HG), as did the distribution volumes values of central (Vc) and peripheral (Vp) compartments (Vc: CG, 0.18 +/- 0.03 L; HG, 0.24 +/- 0.03 L) (Vp: CG, 0.08 +/- 0.05 L; HG, 0.13 +/- 0.05 L). The percentage of theophylline binding to plasma proteins decreased from 44.3% in CG to 33.8% in HG. The theophylline intrinsic clearance (CLint) dropped from 1.35 +/- 0.43 mL/min (CG) to 0.93 +/- 0.10 mL/min (HG)1, which can be attributed to a significant fall in the quantity of hepatic microsomal enzymes. These modifications on the pharmacokinetics of drugs with low hepatic extraction coefficients, such as theophylline, should be considered when dosage regimens during the posthepatectomy hepatic regeneration period are planned.

Contribution of Presystemic Hepatic Extraction to the Low Oral Bioavailability of Green Tea Catechins in Rats

“…Comparing to an average hepatic blood flow of 50 ml/min/kg in rats (Lin, 1990), the tea catechins can be considered to have moderate clearances. The steady state volumes of distribution (V ss ) of these catechins in rats are in the range observed for other polar drugs (Fabre et al, 1977;Maza et al, 1996;Burstein et al, 1999) and are considered to have small distribution volumes. The discrepancies observed between the animal pharmacokinetic data and human situations could be because the oral bioavailability (F) of green tea catechins is also low in humans.…”

Influence of hepatic regeneration after partial hepatectomy on theophylline pharmacokinetics in rats

“…A previous study performed in our laboratory showed that theophylline pharmacokinetics change significantly after hepatectomy (7). However, there are few studies about the influence of hepatic regeneration post-hepatectomy on drug pharmacokinetics.…”

“…The pharmacokinetics of theophylline, a low hepatic clearance drug, has been shown to be altered after partial hepatectomy (7) in rats. In the present study we have studied the influence of hepatic regeneration after partial hepatectomy on the pharmacokinetics of theophylline also in the rat.…”