Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers.

The comparative effect of famotidine or cimetidine on theophylline disposition was determined in healthy volunteers. Cimetidine, but not famotidine, caused a reduction in the rate of elimination of theophylline. The mean total body clearance of theophylline was reduced from 57.6 ml min-1 before cimetidine to 39.5 ml min-1 during cimetidine; and the half-life was prolonged from 8.7 h before cimetidine to 12 h during cimetidine. The volume of distribution and renal excretion of theophylline were not affected by either famotidine or cimetidine.     

Influence of famotidine on verapamil pharmacokinetics in rats.

The effect of famotidine (4 mg/kg, p.o.) on the kinetic profile of co-administered verapamil (20 mg/kg(-1), p.o.) was studied in the rat. Plasma verapamil levels were collected serially for 12 h and measured using sensitive HPLC method. The pharmacokinetic parameters (elimination half-life, area under the plasma concentration-time curve, peak plasma levels and the times to attain these plasma levels) of verapamil were evaluated in the rat. The results indicate that co-administered famotidine did not significantly alter the pharmacokinetic profile of verapamil in the rat. The present finding suggests that famotidine may safely be co-administered with verapamil but clearly further studies in human subjects are needed to reliably rule out the potential interaction of these two drugs.     

No effect of chloroquine on theophylline pharmacokinetics in the rat

The immediate and delayed effects of chloroquine on theophylline kinetics were investigated in rats pretreated with chloroquine diphosphate (45 mg kg⁻¹) or saline intraperitoneally. One hour or 4 days after chloroquine, theophylline (10 mg kg⁻¹) was administered intravenously. Compared with the control animals pretreated with saline, the disposition parameters of theophylline was not altered after pretreatment with chloroquine. Chloroquine did not affect the in vivo metabolism of theophylline in the laboratory rat. A possible decrease in theophylline's volume of distribution at 4 days, but not immediately, after administration of chloroquine was suggested, although this just failed to achieve statistical significance (p = 0.055). Being marginal, it is unlikely to be of clinical concern. It is concluded that, judged from these animal data, there is no evidence of a drug–drug pharmacokinetic interaction for the combination of chloroquine and theophylline. © 1998 John Wiley & Sons, Ltd.     

Effect of hepatic cirrhosis on the pharmacokinetics of theophylline in rats

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethylnitrosamine (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±4.85%) decreased about four-folds, but in DMNA (73.00±9.85%) similar result, was 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.     

Effect of cigarette smoking on theophylline pharmacokinetics in rats.

The effect of acute cigarette smoke inhalation on the plasma levels of theophylline administered orally and parenterally to rats has been studied. The animals were exposed to smoke containing low- or high-nicotine/tar concentration for 10 min immediately after oral, intraperitoneal (i.p.) or intravenous (i.v.) administration of theophylline. The plasma levels of theophylline when administered orally (20 mg kg-1) were lower in the two cigarette smoke-inhaling groups than in the non-smoking restrained control group, with the lowest values in the high-nicotine/tar group. The plasma levels (8 and 12 h after administration) in the high-nicotine/tar group when theophylline was administered i.p. (10 mg kg-1), were also slightly lower than in the non-smoking restrained control group but this was not significant. When theophylline was administered i.v. (5 mg kg-1), there was no difference between the high-nicotine/tar group and the non-smoking restrained control group. These data indicate that cigarette smoke inhalation causes suppression or delay of theophylline absorption from the gastrointestinal tract.     

诺迪康胶囊对茶碱的大鼠体内药物动力学的影响

目的探讨诺迪康胶囊在大鼠体内对茶碱药物动力学的影响。方法16只♂大鼠随机分为实验组和对照组。实验组ig给药诺迪康胶囊1 g.kg-17 d,对照组ig同剂量的生理盐水。第8天ig后30 min,iv氨茶碱(20 mg.kg-1),并于给药前与给药后0.25、0.5、1、2、4、6、8、10、12、24 h不同时间动脉采血,采用HPLC法测定血浆中的茶碱浓度。并比较两组间的药物动力学参数。结果诺迪康胶囊与氨茶碱合用后,在大鼠体内K值显著增大(P<0.05)、t1/2显著缩短(P<0.05)、Vd显著减小(P<0.05),但Cl和AUC无统计学差异(P>0.05)。结论在大鼠体内,诺迪康胶囊可加快茶碱的代谢,临床上合用诺迪康胶囊与茶碱时应监测茶碱的血药浓度。     

Lack of effect of amoxicillin on theophylline pharmacokinetics.

The effect of the antibiotic drug amoxicillin on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 day course of theophylline alone and as obtained during comedication with amoxicillin. Theophylline plasma concentrations were measured by means of h.p.l.c. analysis. On the ninth day of each of the two periods of drug administration a concentration-time curve was evaluated. It showed no influence of amoxicillin on absorption, elimination and volume of distribution of theophylline, as a result of which mean steady state plasma concentrations were not significantly different during both treatments. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.     

Lack of effect of ponsinomycin on the plasma pharmacokinetics of theophylline

Summary The influence of ponsinomycin on the pharmacokinetics of theophylline has been studied in 12 young healthy volunteers. They received 10 doses of theophylline 200 mg every 8 h p.o., successively in the absence and then in the presence of ponsinomycin. This new macrolide, structurally related to midecamycin, was given in the therapeutic dose of 800 mg b.d. for 5 days, starting 2 days before the second phase of treatment with theophylline.The pharmacokinetic parameters of theophylline, calculated from its plasma concentration at steady-state, were not affected by the co-treatment. In particular, there was no significant difference between the peak and trough plasma levels, apparent clearance or apparent elimination half-life of theophylline in the absence and the presence of ponsinomycin. Only renal clearance was slightly (27%) but significantly increased by the co-treatment. The results suggest that ponsinomycin would be a good choice if a macrolide antibiotic were needed in patients being treated with theophylline.     

Lack of effect of flosequinan on the pharmacokinetics of theophylline.

The pharmacokinetics of theophylline (240 mg) p.o. were studied before and after the administration of oral flosequinan for 14 days in 21 healthy volunteers using a randomised cross-over design. Comparisons of Cmax, tmax, AUC, CL of theophylline and urinary recovery of the parent drug and metabolites showed that flosequinan had no significant effect on the disposition of theophylline.     

Comparative study of the effect of famotidine and cimetidine on antipyrine pharmacokinetics in the human

In a randomized order the pharmacokinetics of antipyrine were studied following a 5 days treatment period with placebo, 1000 mg cimetidine and 40 mg famotidine daily, respectively in 7 healthy volunteers. In contrast to cimetidine, famotidine did not significantly affect the disposition of antipyrine in these subjects. Famotidine like the other guanidino-thiazole containing compound tiotidine appears to be free from this unwanted effect on drug metabolism in the liver.     

Lack of effect of atenolol on the pharmacokinetics of theophylline.

The effects of 3 days of pretreatment with cardioselective doses of atenolol on theophylline pharmacokinetics were determined. Nine healthy nonsmoking male volunteers received 6 mg kg-1 i.v. aminophylline under baseline conditions and after both 50 mg day-1 and 100 mg day-1 atenolol. Theophylline clearance, volume of distribution and half-life were not influenced by atenolol pretreatment. These data indicate that cardioselective doses of atenolol do not alter the pharmacokinetics of theophylline.     

氟罗沙星对肺心病人体内茶碱药物动力学的影响

目的：本文研究氟罗沙星对肺心病人体内茶碱药物动力学的影响，为临床合理用药提供依据。方法：应用荧光偏振免疫法分别测定了８名肺心病患者单独静脉滴注氨茶碱及合用氟罗沙星达稳态后茶碱的血药浓度。结果：氟罗沙星明显延长了茶碱的半衰期（Ｐ＜０．０１），使茶碱稳态血药浓度明显升高（Ｐ＜０．０１），清除率降低（Ｐ＜０．０１），分布容积亦明显增大（Ｐ＜０．０１）。结论：氟罗沙星能抑制茶碱的正常代谢，临床上两药合用时应注意氨茶碱剂量的调整。     

The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects.

1. The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2. Subjects were given a single oral dose of theophylline (3.4 mg kg-1), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3. Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 +/- 6.42 ml kg-1 h-1 (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 +/- 0.7 ml kg-1 h-1 (-2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 +/- 3.7 ml kg-1 h-1 (-17.2, -8.1)). 4. Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin. Group A subjects showed only slight inhibition of 1-demethylation (-12.8 +/- 5.5% (-21.5, -4.0)), while group B subjects showed a significantly greater inhibition of 1-demethylation (-49.9 +/- 9.8% (-62.1, -37.7)), 3-demethylation (-44.8 +/- 8.6% (-55.4, -34.1)) and 8-hydroxylation (-27.0 +/- 3.7% (-31.6, -22.4)). 5. The results suggest that inter-individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter-individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4. 6. The interaction between ciprofloxacin and theophylline can be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of repirinast on the pharmacokinetics of theophylline in asthmatic patients

A possible pharmacokinetic interaction between theophylline and repirinast has been investigated in asthmatic patients. The kinetics of theophylline was studied in seven adult in-patients given theophylline 400-800 mg b.d. alone and after three weeks of co-administration of repirinast. There was no effect on the kinetics of the combined treatment.     

Clinical pharmacokinetics of famotidine.

Famotidine is a potent histamine H2-receptor antagonist widely used in the treatment and prevention of peptic ulcer disease. After intravenous administration the plasma famotidine concentration-time profile exhibits a biexponential decay, with a distribution half-life of about 0.18 to 0.5h and an elimination half-life of about 2 to 4h. The volume of distribution of the drug at steady-state ranges from 1.0 to 1.3 L/kg; plasma protein binding is low (15 to 22%). Famotidine is 70% eliminated unchanged into urine after intravenous administration. The total body and renal clearances of famotidine correlate significantly with creatinine clearance. Because its renal clearance (15 L/h) far exceeds the glomerular filtration rate, famotidine is considered to be eliminated not only via glomerular filtration but also via renal tubular secretion. Since its clearance is reduced in patients with renal insufficiency and in elderly patients, the maintenance dosage should be reduced in these patient groups. Removal of famotidine by any of the currently employed blood purification procedures (haemodialysis, peritoneal dialysis and haemofiltration) does not occur to a clinically significant degree. Liver cirrhosis does not appear to affect the disposition of famotidine unless severe renal insufficiency coexists. After oral administration, peak plasma concentrations are attained within 2 to 4h; the oral bioavailability ranges from 40 to 50%, due mainly to incomplete absorption. The oral absorption of the drug is dose-independent within a range of 5 to 40 mg. There are 3 formulations available (tablet, capsule and suspension), which appear to be bioequivalent. Coadministration of potent antacids reduces the oral absorption of famotidine by 20 to 30%. On a weight-to-weight basis, the antisecretory effect of famotidine is about 20 and 7.5 times more potent than those of cimetidine and ranitidine, respectively. Plasma famotidine concentrations correlate with its antisecretory effect: values of about 13 and 20 micrograms/L produce a 50% reduction in the gastrin-stimulated gastric acid secretion and a fasting intragastric pH of greater than 4, respectively. Available data suggest that famotidine interacts neither with the hepatic oxidative drug metabolism nor with the tubular secretion of other commonly used therapeutic agents. However, further studies are required to evaluate a full spectrum of its drug interaction potential.     

Lack of effect of co-trimoxazole on the pharmacokinetics of orally administered theophylline

Eight healthy, male subjects participated in a balanced randomized crossover study to investigate the effect of a course of co-trimoxazole (CT; combination of sulphamethoxazole 800 mg and trimethoprim 160 mg, twice daily for 5 days) on the pharmacokinetics and urinary metabolite profile of an orally administered dose of theophylline (TH). There were no significant differences (p greater than 0.05) between the control and treatment phases with respect to any of the following pharmacokinetic parameters of TH: area under the plasma total TH concentration time curve; fraction unbound in plasma; area under the plasma unbound TH concentration time curve; terminal half-life; apparent volume of distribution; apparent total plasma clearance and renal clearance. The urinary recoveries of 1-methyluric acid, 1.3-dimethyluric acid and of theophylline were not significantly different (p greater than 0.05) between the two study phases. There was a significant difference (p less than 0.05), however, in the urinary recovery of 3-methylxanthine (11.3 +/- 2.6 per cent TH alone versus 13.9 +/- 3.6 per cent TH-CT) and in the total urinary recovery of TH and its metabolites (76.5 +/- 8.2 per cent versus 85.3 +/- 7.0 per cent), the latter finding suggesting that CT may have caused a small increase in the extent of TH absorption. The results of the study indicated that CT did not inhibit the biotransformation of TH.     

Effect of decursinol angelate on the pharmacokinetics of theophylline and its metabolites in rats

Herb-drug interactions represent a serious problem as herbal medicine is used extensively in the modern world. This study investigated the effects of decursinol angelate on the pharmacokinetics of theophylline, a typical substrate of the cytochrome P450 1A2 enzyme, in rats. After 3 days of decursinol angelate pretreatment, on the fourth day, rats were administered decursinol angelate and theophylline concomitantly. Blood theophylline and its major metabolite [1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU)] levels were monitored by liquid chromatography-tandem mass spectroscopy. The results indicated that theophylline clearance significantly decreased and the area under the concentration–time curve (AUC) increased in decursinol angelate (25 mg/kg)-pretreated rats administered theophylline (10 mg/kg). The elimination half-life (t1/2) of theophylline was increased by 20%. In the presence of decursinol angelate (25 mg/kg), the pharmacokinetic parameters of three metabolites (1-MX, 1,3-DMU, and 1-MU) were significantly altered (half-life for 1-MU, and AUC24 h for 1-MX, 1,3-DMU, and 1-MU). Our results suggest that patients receiving CYP1A2-metabolized drugs, such as caffeine and theophylline, should be advised of the potential herb-drug interaction to reduce the risk of therapeutic failure or increased toxicity of conventional drug therapy.     

Lack of effect of pinacidil on theophylline pharmacokinetics and metabolism in man

Pinacidil, a pyridyl cyanoguanidine derivative, is a new antihypertensive vasodilator drug. It shares structural similarities with the histamine H2-receptor blocker cimetidine, an imidazole cyanoguanidine derivative, which is a potent inhibitor of cytochrome P-450 and of theophylline metabolism. In the present study the pharmacokinetics and metabolism of theophylline were determined in six healthy volunteers before and on the last day of oral pinacidil administration for two weeks. The dosage of pinacidil was 12.5 mg twice a day in the first week and 25 mg in the second. There were no significant changes in theophylline plasma clearance, terminal half-life or volume of distribution during pinacidil administration. Also the renal and metabolic clearance of theophylline and the formation clearances of the major theophylline metabolites in the urine (DMU, 1MU, 3MX) did not change significantly during administration of therapeutic doses of pinacidil.     

Lack of effect of withdrawal from cigarette smoking on theophylline pharmacokinetics

The intravenous disposition of theophylline was determined in 12 healthy young male smokers during periods of smoking and short-term withdrawal (24 to 36 hours), using a crossover design. Median half-life, clearance, volume of distribution, hepatic extraction, and intrinsic clearance of theophylline during withdrawal were within +/- 5% of the corresponding median control (smoking) parameters and were normal in comparison with values published for smokers. The lack of change in the pharmacokinetic profile of theophylline indicates that adjustment of the dosage regimen should not be necessary immediately after smoking withdrawal.     

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

The influence of hepatic regeneration after partial hepatectomy on theophylline pharmacokinetics has been studied on the rat. At different times after partial hepatectomy, theophylline was administered intravenously as a single dose of 6 mg/Kg. Drug plasma levels were determined by HPLC and pharmacokinetic parameters were obtained. Physiological parameters were also measured. Following hepatectomy, an increase in mass liver was observed and 15 days after surgery, liver mass was 78% of nonhepatectomized rats. Initial theophylline concentrations varied during the regeneration period, as well as the distribution volume at steady-estate (Vss). Elimination half-life (t 1/2), notably increased after hepatectomy (7.27+/-1.38 h), decreased with time (6.70+/-1.18 h, 6.47+/-0.69 and 5.17+/-0.87 h after 24 h, 3 days and 15 days post-hepatectomy, respectively) to reach a value close to that of the control group (4.30+/-1.37 h). The increase in elimination half-life led to a decrease in the mean residence time during the period of liver regeneration. However, the intrinsic clearance hardly varied during regeneration period. We could establish the following relationship between liver weight (LW) and the elimination half-life: t 1/2 (h)=-0.358*LW (g)+8.6168 (R2=0.9906). For the mean residence time (MRT) this relationship was: MRT (h) =-0.5173*LW (g)+12.433 (R2=0.991).