Pharmacokinetics Of Theophylline In Rats Research Articles

Alteration of the Pharmacokinetics of Theophylline by Paullinia cupana Kunth in Rats

Aims: Paullinia cupana Kunth has been popularly used to prepare different beverages by the Amazonian inhabitants for a long time ago mainly due to its stimulant properties. Although the utilization of this herbal drug has been increasing lately, little is known regarding the possibility of drug interactions. Therefore, this research tried to investigate the effects of the aqueous extract of P. cupana on the pharmacokinetics of theophylline (TPH), a CYP1A marker in rats.
 Methodology: The extract was prepared according to the popular recipe and subjects received different once daily doses of extract (vehicle, 82.1 mg/Kg and 821 mg/Kg) by oral gavage during two weeks. Non-compartimental analysis was carried out to obtain the pharmacokinetic parameters.
 Results: Animals treated with P. cupana (AUC: 1,197.2 ± 284.4 and 346.6 ± 37.0 µg.h/mL for 82.1 and 821 mg/Kg, respectively) had lower exposition to TPH than controls (3,539.48 ± 278.4 µg.h/mL). On the other hand, drug clearance was higher in treated subjects (2.44 ± 0.4 and 7.27 ± 0.7 L/h/kg for 82.1 and 821 mg/Kg, respectively) than controls (0.71 ± 0.0 L/h/kg).
 Conclusion: Therefore, the multiple oral administration of an aqueous extract of P. cupana caused a significant effect on the pharmacokinetics of TPH in rats.

Bioanalytical Study of the Effect of Lycopene on the Pharmacokinetics of Theophylline in Rats

Lycopene, a natural pigment, was reported to have a modulatory effect on cytochrome P450, hence, metabolic clearance of some drugs. This research is concerned with studying the influence of lycopene on the pharmacokinetics of theophylline, a drug with a narrow therapeutic index. Lycopene (10 mg/kg) was intraperitoneally given to rats for eight consecutive days and on the eighth day of treatment, theophylline (5 mg/kg) was intravenously administered. Blood samples were withdrawn from rats at various time periods, treated and analyzed using HPLC. The HPLC method was based on isocratic elution of theophylline and caffeine as internal standard on ZORBAX Eclipse plus C8 column using a mobile phase consisting of water and methanol (80:20, v/v) at a flow rate of 1 mL min-1. Statistical analysis of the pharmacokinetic data using Paired t-test showed a significant decrease in AUC0–t and AUC0-∞ (about 22.140 and 23.824%, respectively,P < 0.05) and a significant increase in Vd and CL (1.28- and 1.40-fold, respectively, P < 0.05) of theophylline administered to rats pretreated with lycopene. Treatment with lycopene has a significant effect on the metabolic clearance and pharmacokinetics of theophylline in rats.

Pharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats

Ethnopharmacological relevanceBaicalin is one of the major bioactive constituents of Scutellariae Radix, the root of Scutellariae baicalensis Georgi and possesses a wide variety of pharmacological properties. Aim of the studyTo elucidate the effect of baicalin on the pharmacokinetics of theophylline in rats, focusing on plasma protein binding displacement and inhibition effect on CYP1A2 in vivo and in vitro. Materials and methodsThe study was a randomized, three-period crossover design. Nine rats were given saline (control) or 450mg/kg baicalin (dosage regimen A or B). Dosage regimen A was administered once at 0h. Dosage regimen B was divided into three dosages (225,112.5, 112.5mg/kg) and was given at 0, 2 and 4h, respectively. Then theophylline (5mg/kg, i.v.) was administered immediately. The effect of baicalin on CYP1A2 activity was determined by metabolism of phenacetin in vitro and plasma protein binding of theophylline was determined by ultrafiltration. ResultsCmax decreased from (12.4±1.6) to (8.7±0.9) and (8.6±2.0)mg/L, T1/2 increased by 116 and 96%, Vd increased by 51 and 49% for total theophylline in rats treated with dosage regimen A and B of baicalin, respectively. Cmax was significantly increased, Vd decreased by 43 and 29% for unbound theophylline in rats treated with dosage regimen A and B of baicalin, respectively (P<0.01). T1/2 of unbound theophylline increased by 104% only in rats treated with dosage regimen B. No significant effects on the CL and AUC of both total and unbound theophylline were observed in the rats treated with dosage regimen A, but the CL decreased and AUC increased for total theophylline and CL decreased for unbound theophylline in the group treated with dosage regimen B (P<0.05). Correlation analysis showed that the mean unbound theophylline (%) and mean baicalin concentration was in good correlation (P<0.01). Baicalin decreased metabolism of phenacetin and exhibited a mixed-type inhibition in rat liver microsomes, with a Ki value of 88.1μM in vitro. Moreover baicalin was a competitive displacer of theophylline from plasma protein in vitro. ConclusionsThe changes in Cmax, T1/2, CL and AUC of theophylline due to baicalin may be attributed to two mechanisms, plasma protein binding displacement and CYP1A2 activity inhibition.

Effects of Ephedra Water Decoction and Cough Tablets containing Ephedra and Liquorice on CYP1A2 and the Pharmacokinetics of Theophylline in Rats

Ephedra water decoction (EWD) and cough tablets containing ephedra and liquorice (maxing cough tablets, MXCT) have been used widely in the treatment of asthma. In the clinic, EWD and MXCT may be prescribed with theophylline, one of the most popular antiasthmatic drugs and a typical substrate of cytochrome P450 (CYP) 1A2. So in the present study the potential effects of EWD and MXCT on CYP1A2 activity and the pharmacokinetics of theophylline in rats were evaluated. In the in vivo CYP1A2 activity research, the rats were given oral caffeine (10 mg/kg) after a 14 day pretreatment with EWD (18 g/kg) and MXCT (0.1, 0.2 or 0.4 g/kg). Then the CYP 1A2 activity was expressed by using the caffeine metabolic ratio (CMR). The results showed that the CMR increased markedly compared with the control groups. In the pharmacokinetics experiment, the rats were given oral theophylline (10 mg/kg) after a 14 day pretreatment with EWD (18 g/kg) and MXCT (0.2 g/kg). The results showed that the AUC(0-24 h) and C(max) of theophylline were reduced markedly compared with the control groups. These results demonstrated that EWD or MXCT pretreatment obviously induced CYP1A2 activity, therefore, speeding up the metabolism of theophylline. The concomitant use of EWD or MXCT may decrease the effect of theophylline in rats.

Pharmacokinetics of theophylline in rats with biliary stasis.

Pharmacokinetics of theophylline in rats with biliary stasis.

Effect of tamoxifen on the pharmacokinetics of theophylline in rats.

The effect of tamoxifen on the pharmacokinetics of theophylline was investigated in male Sprague-Dawley rats. The oral administration of tamoxifen at a dose equal to 40 mg kg-1 48 h before the intravenous injection of theophylline 10 mg kg-1, significantly (P < 0.05) increased the clearance of theophylline by 39%, with no apparent effect on the volume of distribution. As a consequence, the elimination half-life of theophylline was significantly (P < 0.05) shortened in the tamoxifen-treated rats (3.56 +/- 0.39 h vs 5.25 +/- 0.48 h) as well as its mean residence time (5.04 +/- 0.60 h vs 7.50 +/- 0.75 h). Although these data cannot be directly extrapolated to the clinical situation, they provide experimental support to suggest that more attention should be paid to the potential risk of pharmacokinetic interactions in the presence of tamoxifen.

Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU

The types of hepatic cytochrome P450 (CYP) isozymes responsible for the metabolism of theophylline and for the formation of 1,3-dimethyluric acid (1,3-DMU) in rats in-vivo does not seem to have been studied at the dose ranges of dose-independent metabolic disposition of theophylline in rats (up to 10 mg kg(-1)). Therefore, theophylline (5 mg kg(-1)) was administered i.v. to male Sprague-Dawley rats pretreated with various inducers and inhibitors of CYP isozymes. In rats pretreated with 3-methylcholanthrene (3-MC), orphenadrine or dexamethasone (main inducers of CYP1A1/2, CYP2B1/2 and CYP3A1/2, respectively, in rats), the time-averaged non-renal clearance (CLNR) of theophylline was significantly faster than in their respective controls (1260, 42.7 and 69.0% increases, respectively). However, in rats pretreated with troleandomycin (a major inhibitor of CYP3A1/2 in rats), CLNR was significantly slower than in the controls (50.7% decrease). The 24 h urinary excretion of 1,3-DMU was increased significantly only in rats pretreated with 3-MC. The ratio of area under the curve for 1,3-DMU and theophylline (AUC1,3-DMU/AUCtheophylline) was increased significantly in rats pretreated with 3-MC (160% increase) and decreased significantly in rats pretreated with troleandomycin (50.1% decrease); however, the ratio was not increased in rats pretreated with dexamethasone. These data suggest that theophylline is primarily metabolized via CYP1A1/2, CYP2B1/2, and CYP3A1/2, and that 1,3-DMU is primarily formed via CYP1A1/2, and possibly CYP3A1/2, in rats.

Herb–drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats

Herb–drug interaction has become a serious problem since herbal medicine is extensively used in the modern world. This study investigates effects of Andrographis paniculata extract (APE) and its major component, andrographolide (AG), on the pharmacokinetics of theophylline, a typical substrate of cytochrome P450 1A2 enzyme, in rats. After APE or AG pretreatment for 3 days, on the fourth day rats were administered theophylline via femoral vein cannula. The blood theophylline levels were monitored by microdialysis sampling combined with HPLC-UV. The results indicated that the clearance of theophylline was significantly increased and the area under concentration–time curve (AUC) was reduced in both AG and APE pretreated groups at low-dose theophylline administration (1 mg/kg). The elimination half-life ( t 1/2β) and mean residence time (MRT) of theophylline were shortened by 14% and 17%, respectively, in the AG pretreated group when high-dose theophylline (5 mg/kg) was given. However, theophylline accumulated in rat of the group with APE pretreatment. This phenomenon suggests that some other herbal components contained in APE may interact with theophylline and retard its elimination when theophylline was administered at a high dose. Our results suggest that patients who want to use CYP1A2-metabolized drugs such as caffeine and theophylline should be advised of the potential herb–drug interaction, to reduce therapeutic failure or increased toxicity of conventional drug therapy.

Herb–drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats

Herbal medicines have received great attention as alternative medicines in recent years and are also referred to as a dietary supplement or health food. Ginkgo biloba extract (GBE) is one of the most popular herbal medicines. However, little is known about the metabolic interactions between GBE and clinically used drugs. This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window used for the treatment of asthma. Commercial GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30% (GBE 10 mg/kg, P < 0.05) and 70% (GBE 100 mg/kg, P < 0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After oral administration of theophylline (10 mg/kg), the AUC 0–24 h of theophylline was reduced by 40% following pretreatment with GBE (100 mg/kg, P < 0.01). These results demonstrate that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.

Herb–drug interaction of Evodia rutaecarpa extract on the pharmacokinetics of theophylline in rats

The extract of Evodia rutaecarpa fruit and its preparation were used for the treatment of gastrointestinal disorders and headache. To assess the possible herb–drug interaction, the ethanol extract of Evodia rutaecarpa fruit (1 and 2 g/kg/day, p.o.) and the herbal preparation Wu-Chu-Yu-Tang (1 and 5 g/kg/day) were given to rats daily for three consecutive days and on the fourth day theophylline was administered (2 mg/kg, i.v.). Theophylline concentration in blood was measured by a microdialysis coupled to a liquid chromatographic system. Pharmacokinetic data were calculated by noncompartmental model. The results indicate that the theophylline level was significantly decreased by the pretreatment with the extract of Evodia rutaecarpa and herbal preparation Wu-Chu-Yu-Tang with dose-related manner. It is suggested that the herb–drug interaction may occur through the induction of the metabolism of theophylline.

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.

Influence of a newly developed quinolone, T-3761, on pharmacokinetics of theophylline in rats

The effect of a new quinolone, T-3761, on the pharmacokinetics and metabolism of theophylline was investigated with rats. T-3761 at a high dose (20 mg/kg of body weight) was injected intravenously 10 min before an intravenous administration of theophylline (10 mg/kg). The presence of T-3761 slightly delayed the disappearance of theophylline from plasma. Parameters related to the pharmacokinetic interaction between theophylline and T-3761 were estimated by noncompartmental methods. A significant decrease (approximately 25%) in the systemic clearance of theophylline was observed in the presence of T-3761. However, no significant changes between the control group and the T-3761-treated groups in the volume of distribution at a steady state were observed. Pretreatment with T-3761 increased the urinary excretion of unchanged theophylline (by approximately 25%) and decreased the nonrenal clearances (by approximately 30%), indicating that T-3761 inhibits the metabolism of theophylline. These findings suggest that T-3761 at the dose used in this study affects the pharmacokinetics and metabolism of theophylline.

Effect of sparfloxacin on pharmacokinetics of theophylline in rats.

The effect of sparfloxacin on the theophylline pharmacokinetics was investigated in rats.1. The plasma levels and pharmacokinetic parameters of theophylline after a single oral dose (15mg/kg) in rats treated orally with sparfloxacin (100 mg/kg, 3 times) were not significant different from those in control rats, not treated with sparfloxacin.2. After multiple oral administration of theophylline (15mg/kg, twice/day) for 3 days, the maximum plasma concentration of theophylline was 20.2μg/ml in the sparfloxacin-treated rats (100mg/kg, 3 times/day for 3 days) and 21.0μg/ml in the control rats, and there was no effect of the sparfloxacin treatment.3. In the 24-hr urinary excretion of theophylline after a single oral dose (15mg/kg), there was no significant difference between the sparfloxacin-treated (100mg/kg, 3 times) and control rats. Moreover, the sparfloxacin treatment also did not affect the amount of the theophylline metabolites excreted in urine.4. In conclusion, sparfloxacin shows no significant effect on the pharmacokinetics of theophylline in rats.

Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats.

The effects of cimetidine and a new, potent H2-antagonist, famotidine, on the single dose pharmacokinetics of theophylline were examined in rats. Male Sprague-Dawley rats (6 rats/group) received an i.v. dose of theophylline (6 mg/kg) alone and in conjunction with an i.v. dose of famotidine (10 mg/kg) or cimetidine (10 mg/kg). Venous blood samples were collected serially for seven hours after theophylline infusion and analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0- infinity; 38.1 +/- 8.7 vs. 38.8 +/- 6.3 micrograms.hr.ml-1), while cimetidine demonstrated a significant reduction in theophylline systemic clearance (0.11 +/- 0.02 vs. 0.16 +/- 0.02 L/hr/kg; p less than 0.001), a 40% prolongation of half-life (2.8 +/- 0.9 vs. 2.0 +/- 0.5 hr), with no change in the volume of distribution (0.39 +/- 0.1 vs. 0.41 +/- 0.13 L/kg). These results suggest that in contrast to cimetidine, famotidine, a non-imidazole H2-receptor antagonist, does not interfere with theophylline disposition in the rat.

Dose-dependent elimination of theophylline in rats.

The effect of different doses on the rate of metabolism of theophylline in rats was investigated. After doses of 52 or 115 mg/kg, the initial concn. decayed according to a first-order process with an apparent half-life of about four hours. However, after four to eight hours the slope of the curves declined, resulting in elimination half-lives of about 70 min. Similar half-lives of 70 min were also found after doses of 6 or 11 mg/kg. The AUC increased disproportionately with dose, indicating capacity-limited elimination. No differences were observed in capacity-limited elimination of the two major metabolites of theophylline: the ratio between the amounts of 1,3-dimethyluric acid and 1-methyluric acid formed was independent of the dose of theophylline. The initial apparent first-order decay after higher doses resulted from a combination of capacity-limited metabolism and compensatory increased diuresis of unchanged theophylline. It is concluded that linear pharmacokinetics of theophylline in rats apply only to doses not exceeding 10 mg/kg.