• Archives of Pharmacal Research
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• v.20 no.4
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• pp.318-323
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• 1997

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethyinitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life $(t_{1/2})$ in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL $(8.67{\pm}4.85%)$ decreased about four-folds, but in DMNA $(73.00{\pm}9.85%)$ similar result war observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.

• Korean Journal of Clinical Pharmacy
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• v.2 no.1
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• pp.23-28
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• 1992

This study was attempted to investigate the pharmacokinetics of theophylline(4mg/kg) in the rabbits of carbon tetrachloride induced hepatic Cailure, The plasma concentration and relative bioavailability of theophylline were increased significantly in hepatic railure rabbits compared with those of normal rabbits. There was significant relationship between SGOT value and bioavailability parameters of theophylline. From the results of this experiments, dosage regimen of theophylline is considered to be adjusted in dose size and dosing interval using SGOT values.

• YAKHAK HOEJI
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• v.35 no.5
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• pp.379-383
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• 1991

This study was attempted to investgate the pharmacokinetics of theophylline (4 mg/kg i.v) in the rabbits pretreated with propranolol (1 and 2.5 mg/kg/hr, infusion) for four hours. The plasma concentration and AUC of theophylline were increased in rabbits pretreated with propranolol as compared with those of normal rabbits. The amount of cumulative urinary excretion and renal clearance and total body clearance were decreased in rabbits pretreated with propranolol as compared with those of normal rabbits. The apparent volume of distribution was slightly affected by change of the clearance of theophylline. From the results of this experiment, it is desirable that dosage regimen of theophylline should be adjusted when theophylline combined with propranolol in clinical pharmacy practice.

• YAKHAK HOEJI
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• v.35 no.1
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• pp.38-44
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• 1991

It has been reported that the pharmacokinetic behaviors of drugs which are mostly metabolized in the liver are significantly different in patients with renal failure. Theophylline(TP) is mainly metabolized in the liver (approximately 90%) and renal clearance of the drug is negligible (less than 10%). Therefore, we have investigated the changes in pharmacokinetics of theophylline in normal, G-ARF and U-ARF rats after an intravenous administration. The total body clearance of TP decreased approximately 40% in U-ARF rats. The reduced CL$_{T}$, value in U-ARF rats could be due to reduced hepatic intrinsic clearance by up to 40% since it has been published that plasma protein binding of TP and liver blood flow does not change in U-ARF rats.

• Toxicological Research
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• v.4 no.1
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• pp.1-12
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• 1988

In order to evaluate the effect of cigarette smoking on the pharmacokinetics of theophylline in Koreans, doses of 4.5 to 5.0 mg/kg of theophylline, as injectable aminophylline, were administered to 12 normal young volunteers (male, 22 to 35 yrs;mean, 26 yrs) through intravenous infusion over 30 minutes, and pharmacokinetics of theophylline were tested. Among subjects, six were nonsmokers and the other were smokers (range 1 to 2 packs/day). Also the correlations between plasma and saliva theophylline concentrations were investigated by determining the concentrations of theophylline in saliva simultaneously at each plasma sampling time. The total body clearances of theophylline in smokers (Mean${\pm}$SD, 0.0578${\pm}$0.0092 L/hr/kg)were appreciably higher than thoxe of nonsmokers (Mean${\pm}$SD, 0.0359${\pm}$0.0063 L/hr/kg), and the half-lives of theophylline in smokers averaged 5.36${\pm}$1.22hr, and significantly shorter than those of nonsmokers which averaged 9.14${\pm}$1.73hrs(p<0.005). But the apparent volumes of distribution of theophylline did not show any significant difference between smokers (Mean${\pm}$SD,0.44 ${\pm}$0.05L/kg) and nonsmokers (Mean${\pm}$SD, 0.46${\pm}$0.05L/kg). The average concentration ratios in saliva and plasma were 0.61 in smokers and 0.56 in nonsmokers after 2 hrs following drug administrations, and the smoker group had a slightly higher value of ratio(S/P) than the nonsmoker group (p<0.05). The correlations between saliva and plasma theophylline concentration in smokers were r=0.852(p<0.0005) within 2 hr and r=0.985(p<0.0005) after 2 hrs and also those of nonsmokers were r=0.729(p<0.0005) within 2 hrs and r=0.957(p<0.0005) after 2 hrs starting the infusion. From the results, it was found that smoking cigarettes had significantly increased the clearance of theophylline and that the relationships between saliva and plasma theophylline concentrations in all subjects were better after 2 hrs than within 2 hrs starting the infusion of aminophlline.

• Korean Journal of Clinical Pharmacy
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• v.17 no.1
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• pp.13-18
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• 2007

The purpose of the present study was to investigate the effect of cimetidine on theophylline pharmacokinetics in Korean healthy normal subjects. Eight subjects were enrolled and open label, two period cross-over study was conducted without significant drug related adverse reactions. Cimetidine seemed that significantly inhibited the metabolism of theophylline, oral clearance decreased significantly when cimetidine was coadministered. Coadministered cimetidine increased $AUC_t$ and $C_{max}$ of theophylline. All subjects were genotyped using PCR-RFLP methods to evaluate the differences in metabolic capacity in accordance with CYP1A2 genotypes, but no mutant genotype was found. This suggests that metabolic capacities were not significantly affected by CYP1A2 genotypes among subjects. In conclusion, disposition of theophylline was significantly affected by coadministered cimetidine. Further evaluation with well-designed drug interaction study in accordance with various genotype of CYP1A2 is needed.

• Tuberculosis and Respiratory Diseases
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• v.44 no.5
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• pp.992-1000
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• 1997

Background : Since up to 90% of a theophylline dose is biotransformed, probably by interaction with one or more the variants of the cytochrome P-450 drug metabolism system, anti-tuberculosis agents including drugs influencing microsomal enzyme systems, such as isoniazid and rifampicin. may be affect the elimination of theophylline. Method : The effect of combination therapy with isoniazid(INH), rifampicin(RFP), ethambutol(EMB) and pyrazinamide(PZA) on the pharmacokinetics of theophylline was evaluated by a computer program using Bayesian method. Three group were divided as follows. Group I is control, Group II is treated with INH. RFP, EMB and PZA and Group III is treated with INH, RFP and EMB. All of them were ilon-smoker who were normal in liver and renal functions, and not administered drugs affecting on the clearance of theophylline with exception of anti-tuberculous agents. Results : When it compared control with test groups, the clearance of theophylline in Group II and Group III was significantly decreased(p<0.001), and half life in Group II and Group III showed significant elevation(p<0.001). However there were no significant differences in clearance and half life between the Group II and Group III. Conclusion : These results suggest that theophylline dose may be need of readjustment in concurrent medication of anti-tuberculous agents including INH, RFP, and EMB.

• Korean Journal of Clinical Pharmacy
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• v.10 no.3
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• pp.107-110
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• 2000

Theophylline and $\beta$-adrenergic agonists are frequently used together in patients with respiratory diseases. However the clinical impact of $\beta_2$-adrenergic agonists on the blood concentration of theophylline is not fully evaluated. Formoterol, a newly available oral ${\beta}_2$-adrenergic agonist is frequently used in pediatric respiratory patients. The objective of this study was to investigate the effect of oral formoterol on theophylline's blood concentration. Randomized prospective study was conducted. Twenty-four children were enrolled on the study. Their age ranged 2 to 73 months (mean 35.8 months). Theophylline group (12 patients) received 10 mg/kg/day of for theophylline orally. Theophylline/formoterol group (12 patients) received 10 mg/kg/day of theophylline and $4\;{\mu}g/kg/day$ of formoterol orally. All medications were administered at least for 5 days starting on admission day. Theophylline's trough concentrations were obtained on days 3 and day 5. Pulse rates were recorded before the study medications were given on admission, and days 3 and day 5. Statistical significance was calculated by two-tailed Student's t-test. Theophylline's levels in children given theophylline and formoterol together were lower an those given theophylline alone ($6.38\pm0.90\;{\mu}g/ml\;vs\;7.43\pm0.77\;{\mu}g/ml$ on day 3(p<0.05), $5.62\pm0.56\;{\mu}g/ml\;vs.\;6.78\pm0.61\;{\mu}g/ml$ on day 5 (p<0.05)). In both groups, theophylline's trough concentration on day 5 were lower than day 3. There was no significant side effects in both groups. In conclusion, the new ${\beta}_2$ selective adrenergic agonist formoterol reduced serum theophylline levels in children with respiratory diseases. Further investigation is needed to clarify the long term effect of this drug interaction.

• Korean Journal of Clinical Pharmacy
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• v.9 no.1
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• pp.55-61
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• 1999

The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride treatment when aminophylline (8 mg/kg as theophylline, i.v.) was injected. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dimethyluric acid from theophylline in microsomes was determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to $17\%$ of the control value while AUC (area under the plasma concentration-time curve) and $(t_{1/2})_{\beta}$ were increased to about 6 fold and 10 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to $33-41\%$ of the control value in microsomes of cirrhotic rat liver. From these results, it can be concluded that in cirrhotic rats induced by N,N-dimethylnitrosamine or carbon tetrachloride the total body clearance of theophylline is markedly reduced due to a reduced hepatic metabolism.

• 대한임상약리학회:학술대회논문집
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• 2006.11a
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• pp.80-80
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• 2006