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.

INVESTIGATING EFFECTS OF 7,8-DISUBSTITUTED DERIVATIVE OF THEOPHYLLINE (BENOPHYLLINE) ON FREE-RADICAL OXIDATION IN RENAL INJURY OF RATS

This article highlights the pharmacological study of new 7,8-disubstituted derivative of theophylline, the substance conditionally named benophylline. Based on the literature data and previous studies of compounds of this class, it has been concluded that studying the effect of benophylline on the pro-antioxidant system under simulated pathologies is of great interest and importance.
 The study of antihypoxic action of 7,8-disubstituted theophylline in rats was carried out under modelled normobaric hypoxia with hypercapnia (in an enclosed space). It has been found out the application of 7-n-methylbenzyl-8-substituted polyphosphonates increases the longevity of rats in the conditions described above that evidences the improvement of metabolic processes in mitochondrial respiratory chain.
 Based on the results of screening studies, we selected 7,8-disubstituted derivative of theophylline (benophylline) as a leading substance for further investigation. The purpose of the study was to evaluate the efficacy of benophylline for the pharmacological correction of free radical processes in experimental renal damage in rats based on the evaluation of the expression of lipid peroxidation and antioxidant protection.
 Materials and methods: blood serum, homogenate and rat kidney tissues were the study materials. The study of the protective effect of benophylline on the functional state of the kidneys was investigated on experimental model of acute renal injury by introducing 50% water solution of glycerol (myoglobin nephropathy). Pathogenesis of this model was described in the methodological recommendations by C. Yu. Shtrygol, V. M. Lysovoi, I. A. Zupanetz et al. in «Methods of experimental modeling of kidney damage for pharmacological research». The content of TBK-R was determined spectrophotometrically by reaction with thiobarbituric acid.
 Glutathione recovered activity was determined spectrophotometrically in reaction with Elman's reagent using the method of Beutler E. D. et al. The catalase activity was assessed by the method of M.A. Koroluk et al. The influence of benophylline on the morphological state of the renal parenchyma was assessed on the modeled myoglobin nephropathy. The activity of gamma-glutamyltranspeptidase in serum was evaluated photometrically using a reagent test kit (“Filisit”). Statistical processing of the results was performed using the STATISTICA 8.0 software package, with the mean value, standard error of the mean confidence interval (p≤0.05). The microscopic study of microproducts was performed under the Granum microscope. Micrographs were taken with a Granum DMC 310 digital camera. The images were processed on a Pentium 2.4 GHz computer using Toup View software.
 Research results: Under the influence of benophylline, the processes of LPO and AOP became normalized, the expressiveness of degradation of the nephrocytes decreased, the microscopic picture of renal excretion in all rats got normalized. At the same time, 62.5% of the rats had the morphological condition of kidneys close to the intact control, and 37.5% of the animals were noticed to demonstrate a significant decrease in the dyscirculatory abnormalities, inflammatory manifestations and signs of nephrocyte regeneration.
 Conclusions: The ability of benophylline to inhibit the processes of free radical oxidation and to enhance antioxidant protection has been found out. The study has shown benophylline enhances regenerative effect kidney tissues.

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.

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation.

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.

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:In VivoandIn VitroEffect of Shenmai Injection, a Herbal Preparation, on the Metabolic Activities of Hepatic Cytochrome P450 3A1/2, 2C6, 1A2, and 2E1 in Rats

Shenmai injection (SMI), a mixture of Radix Ginseng and Radix Ophiopogonis, is one of the most popular herbal medicinal products and is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of SMI, in vivo and in vitro, on the metabolic activities of hepatic cytochrome CYP450 3A1/2, 2C6, 2E1, and 1A2 in rats. After a single or multiple pretreatment with SMI, the rats were administrated intravenously a cocktail containing midazolam (1 mg/kg), diclofenac (0.5 mg/kg), theophylline (1 mg/kg), and chlorzoxazone (0.5 mg/kg) as probe substrates of rat CYP450 3A1/2, 2C6, 1A2, and 2E1, respectively. Single and multiple SMI pretreatment to rats resulted in a rise of 33.8 % (p < 0.01) and 25.6 % (p < 0.01) in AUC for midazolam, and an increase in AUC for diclofenac by 14.7 % (p < 0.05) and 31.2 % (p < 0.01), respectively. However, the pharmacokinetics of chlorzoxazone and theophylline in rats was not altered markedly. In rat liver microsomes, linear mixed-type inhibition of SMI against the enzyme activities of CYP3A1/2, CYP2C6, and CYP1A2 was shown with IC(50) values of 3.3 %, 2.0 %, and 3.1 % and K(i) values of 3.8 %, 1.5 %. and 1.9 %, respectively. These in vivo and in vitro results demonstrated that SMI had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats.

Pharmacokinetic and pharmacodynamic study of interaction of Rhodiola rosea SHR‐5 extract with warfarin and theophylline in rats

Significant pharmacokinetic/pharmacodynamic interactions between various herbal products and drugs being substrates of cytochrome P450 have recently been reported. The aim of this study was to determine whether Rhodiola rosea SHR-5 extract interacts with warfarin and theophylline when administered concomitantly. Thus, concomitant treatment of rats with theophylline and SHR-5 did not give rise to significant effects on the pharmacokinetics of theophylline. Simultaneous administration of SHR-5 and warfarin did not alter significantly the pharmacokinetics or the anticoagulant activity of warfarin. It is concluded that SHR-5 might be of value in the treatment of patients with mild or moderate depression, and that its interaction with co-administered drugs is likely to be negligible.

The effect of coenzyme Q10 on the pharmacokinetic parameters of theophylline

Interaction of a drug with other drugs and dietary supplements is becoming an emerging issue for patients and health insurance authorities due to awareness of adverse drug event. In this study, we examined the effects of coenzyme Q10 (CoQ10), one of the most popular dietary supplements, on the pharmacokinetic parameters of theophylline in rats. The pharmacokinetic parameters of theophylline changed significantly when the drug was administered after five consecutive days of pretreatment with CoQ10. Time to reach maximum plasma concentration of theophylline delayed when the drug was administered after the pretreatment with CoQ10. Maximum plasma concentration and area under the curve of theophylline were about two-fold increased and other pharmacokinetic parameters such as half-life and volume of distribution were also changed significantly. Therefore, although CoQ10 is generally considered a safe dietary supplement, it appears that patients on theophylline therapy should use caution when they take CoQ10.

Anti-inflammatory Effect of Theophylline in Rats and Its Involvement of the Glucocorticoid–Glucocorticoid Receptor System

Although theophylline has been suggested to have an anti-inflammatory effect, there have been few reports to show the in vivo effect and the mechanism of anti-inflammatory activity of theophylline experimentally. To reveal the anti-inflammatory activity of theophylline, we studied the effect of theophylline and its metabolites on carrageenan-induced edema in rat foot pad. Subcutaneous injection of theophylline (5 –100 mg/kg) inhibited carrageenan-induced edema dose-dependently. Theophylline metabolites, that is, 1-methylxanthine, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid (equimolar dose to 50 mg/kg of theophylline), did not inhibit the edema significantly. The inhibitory effect of theophylline on carrageenan-induced edema disappeared by pretreatment with aminoglutethimide, an inhibitor of glucocorticoid synthesis and with mefepristone, an antagonist of the glucocorticoid receptor. These results suggest that theophylline itself has anti-inflammatory activity and the glucocorticoid–glucocorticoid receptor system is involved in the anti-inflammatory activity of theophylline.

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.

The Effect of 1-Furan-2-yl-3-pyridine-2-yl-propenone on Pharmacokinetic Parameters of Theophylline

The pharmacokinetic parameters of theophylline in rats did not change significantly when the drug was intravenously administered after three consecutive days of pretreatment with 17 mg/kg, orally, of 1-furan-2-yl-3-pyridine-2-yl-propenone (FPP-3), an investigatory drug having dual inhibitory action on cyclooxygenase (COX) and 5-lipoxygenase (5-LOX). However, significant changes were found in the pharmacokinetic parameters of the drug at doses of 34 mg/kg and more of FPP-3. Results of cytochrome P450 activity test indicated that the alteration in pharmacokinetic parameters of the drug appears to be due to the inhibitory effect of FPP-3 on cytochrome P450 1A which is responsible for the metabolism of theophylline. Methoxyresorufin-O-demethylase (MROD) and ethoxyresorufin-O-deethylase (EROD) activity assays revealed that the relative activities of cytochrome P450 1A1 and 1A2 were dose-dependently reduced in the presence of 1, 5, and 10 microM FPP-3 concentrations. Taking into consideration that FPP-3 is intended to be primarily used by geriatric patients with chronic diseases and therefore may be used in long-term basis, the investigatory drug needs to be assessed thoroughly in terms of drug interaction with other commonly prescribed medications.

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.

Extension of the Isobolographic Approach to Interactions Studies Between More than Two Drugs: Illustration with the Convulsant Interaction between Pefloxacin, Norfloxacin, and Theophylline in Rats

This work proposes a model to characterize the additivity or the nonadditivity of combinations of more than two agents. Using a Bayesian framework, we modeled the variability between experimental subjects, the errors that occurred during data collection, and the relationship between effects and concentrations of agents at the effect site. The model was used to characterize the additivity (or non-additivity) of norfloxacin, pefloxacin, and theophylline in causing maximal seizures in male Sprague Dawley rats. Animals received the drugs separately or in various combinations. Drug infusion was stopped at the onset of maximal seizures, and cerebrospinal fluid samples were collected for determination of drug concentration by high-performance liquid chromatography. The model was fitted to concentration data using Markov Chain Monte Carlo techniques. Results showed that induction of seizures by mixtures of theophylline and pefloxacin were additive. Seizure induction by mixtures of norfloxacin and pefloxacin or norfloxacin and theophylline were not additive and, given the model, these drugs interacted negatively. There was no triple interaction effect between the drugs. This study demonstrates the ease with which mixtures of more than two drugs can be analyzed with the proposed model. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Benefit of theophylline administration in tacrolimus-induced nephrotoxicity in rats.

Tacrolimus (TAC), a widely used nephrotoxic calcineurin inhibitor, is associated with renal vasoconstriction possibly through adenosine receptor activation. Theophylline (THEO), an adenosine receptor inhibitor, protects against the nephrotoxicity of drugs associated with renal vasoconstriction. We hypothesized that coadministration of low dose THEO in rats would prevent TAC-induced nephrotoxicity. Sprague-Dawley rats pair-fed a low-sodium diet were randomized into three groups ( n=10/group): the control (CONTROL) group received the vehicle for both medications; the TAC group received TAC 6 mg/kg/day and vehicle; and the TAC+THEO group received TAC and THEO 17 mg/kg/day. On day 21, a timed urine collection was obtained for creatinine clearance. On day 22, serum creatinine, THEO and whole blood TAC concentrations were determined. One kidney was removed for formalin fixation and histological assessment. In the TAC group, serum creatinine increased while creatinine clearance decreased compared to CONTROL (0.3+/-0.0 vs. 0.4+/-0.0 mg/dl and 0.53+/-0.06 vs. 0.34+/-0.04 ml/min/100 g body weight respectively, p<0.05), while TAC+THEO did not differ from control. There were no significant differences in renal histology. Concurrent administration of low-dose THEO prevented the TAC-induced decline in renal function, consistent with a role for adenosine in TAC-induced nephrotoxicity.

Morphological Changes in Salivary Glands Induced by Theophylline in Rats

Theophylline, a phosphodiesterase inhibitor, is known to induce enlargement of the salivary glands. This enlargement has been thought to be associated with enhanced cellular levels of cyclic AMP as a result of inhibition of phosphodiesterase. In the present study, to clarify the sequential changes in salivary glands following the administration of theophylline, a four-day repeated dose study and a single dose study were carried out in male rats, and the parotid and submaxillary glands were examined histologically. The results from the glands were almost identical. In the repeated dose study, the increased organ weight just before the last administration was reduced at 4 hr and then restored at 8 hr after the last administration. In the single dose study, a slight but significant increase in organ weight was observed at 24 hr after administration, following a transient reduction. Changes in acinus histology were consistent with these organ weight changes. Acinar cells were loaded with excessive secretory granules just before the last administration in the repeated dose study. After the last administration, granules were reduced at 4 hr, and then reaccumulated at 8 hr. Such time-course variability in the number of secretory granules corresponded well to clinically observed salivation. These results suggest that inhibition of phosphodiesterase is primarily involved in the discharge of secretory granules, and that the salivary hypertrophy previously reported is an adaptive response caused by the repeated stimulation of saliva secretion.