Differences in Theophylline Clearance between Patients with Chronic Hepatitis and Those with Liver Cirrhosis

Yasuo Kurata, Shota Muraki, Yushi Kashihara, Takeshi Hirota, Hiroshi Araki, Ichiro Ieiri

Research output: Contribution to journalArticlepeer-review

Abstract

Background:Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis.Methods:The authors retrospectively obtained 496 trough concentrations of theophylline at steady state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into 3 categories: Normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, coadministration of clarithromycin (CAM), and sex were considered as covariates that affected theophylline clearance.Results:Theophylline clearance (CL/F per kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/h·kg-1) = 0.0484 × 1.40SMK× 0.861CAM× 0.889CH× 0.557LC. Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that CL/F in CH and LC patients was 0.043 and 0.027 L/h/kg, respectively, and it was lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in those with CH may be due to a decrease in the metabolic enzymatic capability of LC patients.Conclusions:Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.

Original languageEnglish
Pages (from-to)829-834
Number of pages6
JournalTherapeutic drug monitoring
Volume42
Issue number6
DOIs
Publication statusPublished - Dec 2020

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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