INFLUENCE OF PARTIAL-HEPATECTOMY ON THEOPHYLLINE PHARMACOKINETICS IN RATS

The influence of partial hepatectomy on the pharmacokinetics of theoph ylline was determined in rats. The pharmacokinetics of intravenous the ophylline was studied in unhepatectomized rats (control group: CG) and in hepatectomized rats (HG) 12 h after 70% hepatectomy. Liver functio n was monitored in both groups by measurements of total and direct bil irubin, transaminases GOT and GPT, and plasma protein. Seventy per cen t hepatectomy caused significant liver dysfunction: transaminase level s (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 sig nificantly 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 (V-c ) and peripheral (V-p) compartments (V-c: CG, 0.18 +/- 0.03 L; HG, 0.2 4 +/- 0.03 L) (V-p: CG, 0.08 +/- 0.05 L; HG, 0.13 +/- 0.05 L). The per centage of theophylline binding to plasma proteins decreased from 44.3 % in CG to 33.8% in HG. The theophylline intrinsic clearance (CL(int)) dropped from 1.35 +/- 0.43 mL/min (CG) to 0.93 +/- 0.10 mL/min (HG), which can be attributed to a significant fall in the quantity of hepat ic 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 h epatic regeneration period are planned.