Influence of Partial Hepatectomy on Theophylline Pharmacokinetics in Rats

• Published in: Journal of pharmaceutical sciences Vol. 85; no. 10; pp. 1133 - 1135
• Main Authors: Maza, A., Gascón, A.R., Calvo, M.B., Hernández, R.M., Pedraz, J.L.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.10.1996; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Animals; Bilirubin - blood; Biological and medical sciences; Bronchodilator Agents - pharmacokinetics; General pharmacology; Half-Life; Hepatectomy; Liver Diseases - metabolism; Liver Diseases - surgery; Liver Regeneration; Male; Medical sciences; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Rats; Rats, Wistar; Theophylline - administration & dosage; Theophylline - metabolism; Theophylline - pharmacokinetics; Transaminases - blood; Vasodilator Agents - pharmacokinetics; Vertebrata; Mammalia; Intravenous administration; Rat; Surgery; Animal; Rodentia; Theophyllin; Xanthine derivatives; Pharmacokinetics; Hepatectomy
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js9600989

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) 12h 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±0.57h (CG) to 7.08±0.69h (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±0.43mL/min (CG) to 0.93±0.10mL/min (HG), 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.