Theophylline Clearance Research Articles

Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor.

Zileuton, a 5-lipoxygenase inhibitor, was evaluated as an inhibitor of cytochrome P450 activity in human liver microsomes. In the absence of preincubation, the racemate was found to be a weak inhibitor (IC50 > 100 microM) of phenacetin O-deethylation (POD) (CYP1A2), paclitaxel 6alpha-hydroxylation (CYP2C8), diclofenac 4'-hydroxylation (CYP2C9), (S)-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), testosterone 6beta-hydroxylation (CYP3A4), chlorzoxazone 6-hydroxylation (CYP2E1), and bupropion hydroxylation (CYP2B6). When preincubated with NADPH-fortified human liver microsomes in the absence of substrate, zileuton (racemate) was shown to inhibit POD. The effect was NADPH-, time-, and concentration-dependent, and was characterized by a kinact (maximal rate of enzyme inactivation) and apparent KI(inhibitor concentration that supports half the maximal rate of inactivation) of 0.035 min(-1) and 117 microM, respectively (kinact/KIratio of 0.0003 min-1 microM(-1)). Preincubation-dependent inhibition of POD activity was also observed with the individual (S)-(-)- and (R)-(+)-enantiomers of zileuton [(S)-(-)-zileuton; kinact, 0.037 min(-1), KI, 98.2 microM, kinact/KIratio, 0.0004 min(-1) microM(-1); (R)-(+)-zileuton; kinact, 0.012 min(-1), KI, 66.6 microM, kinact/KIratio, 0.0002 min(-1) microM(-1)]. In addition, the inhibition of CYP1A2 was not reversed in the presence of reduced glutathione, catalase, and superoxide dismutase and was refractory to dialysis. Therefore, zileuton was characterized as a mechanism-based inhibitor of human liver microsomal CYP1A2. Mechanism-based inhibition of CYP1A2 may explain why zileuton decreases the oral clearance of antipyrine, propranolol, (R)-warfarin, and theophylline, at doses that have a minimal effect on the pharmacokinetics of (S)-warfarin, phenytoin, and terfenadine.

An Evaluation of the Dose‐Dependent Inhibition of CYP1A2 by Rofecoxib Using Theophylline as a CYP1A2 Probe

This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two-way, randomized, crossover fashion and administered a single oral 300-mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC infinity and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.

Polymorphisms in the CYP1A2 gene and theophylline metabolism in patients with asthma

Cytochrome p450 (CYP) 1A2 gene polymorphisms are thought to be involved in theophylline metabolism. We analyzed the effect of genetic polymorphisms in the 5'-flanking region to the first intron of the CYP1A2 gene on theophylline metabolism in 75 Japanese patients with asthma and 159 healthy Japanese volunteers. Genetic polymorphisms were detected at 4 sites of the CYP1A2 gene, -2964(G/A) and -1569(T/del) in the 5'-flanking region and 155(T/G) and 731(A/C) in the first intron. There were no significant differences in the distribution of gene polymorphisms between the asthmatic and control groups. Among asthmatic patients, theophylline clearance was significantly lower in patients with the polymorphism at site -2964(G/A) whose genotype was G/A (0.029 +/- 0.001 L x h(-1) x kg(-1)) or A/A (0.029 +/- 0.002 L x h(-1) x kg(-1)) than in those whose genotype was G/G (0.034 +/- 0.001 L x h(-1) x kg(-1)) (P <.01 and P <.05, respectively). High theophylline clearance levels significantly correlated with age in the G/G subgroup of site -2964(G/A) (P <.05, r = -0.35) but not in the G/A or A/A subgroup. Given its potential side effects, theophylline may need to be used with care in patients with the A allele at site -2964(G/A) in the CYP1A2 gene, because theophylline metabolism levels are lower in such patients, particularly in young asthmatic individuals.

Developmental changes in the liver weight- and body weight-normalized clearance of theophylline, phenytoin and cyclosporine in children.

Body weight- (BW) normalized pediatric dosages of metabolically eliminated drugs often exceed the corresponding adult values. We aimed to clarify whether such findings would be attributable either to an augmented hepatic drug-metabolizing activity or to a systematic bias introduced by adopting BW as a size standard of clearance. We chose 3 model drugs that are metabolized by distinct cytochrome P450 (CYP) isoforms (theophylline, phenytoin and cyclosporine for CYPIA2, CYP2C9/2C19 and CYP3A4, respectively). The MEDLINE database covering 1966 to May 2001, was searched for articles where systemic clearance oftheophylline or oral clearance of cyclosporine and Vmax/ Km of phenytoin were reported with demographic data of individual children. Liver weights (LWs) of children were estimated using the equation constructed based upon the autopsy data in literature, and body surface area (BSA) was calculated using a standard formula. Relationships between age and clearance of the 3 model drugs that were normalized against BW, LW and BSA were examined. The analysis was confined to the data obtained from children older than 1 year due to scarcity of data for infants and neonates. Relevant data were obtained from 24, 46 and 14 children for theophylline, phenytoin and cyclosporine, respectively. The development of LW lags behind that of BW but is almost identical to that of BSA. Thus, children had a greater LW/BW ratio than adults. The BW-normalized clearance of theophylline and Vmax/Km of phenytoin showed significantly (p < 0.01) negative correlations with age (r = -0.43 and -0.50, respectively) during childhood, whereas their LW- or BSA-normalized clearances were independent of age. While our analyses were made upon limited numbers of subjects and range of age, the results suggest that children appear to have an augmented BW-normalized clearance for drugs of which metabolism is dominated by the CYP1A2, CYP2C9 or CYP3A4 due mainly to a lagged development of BW than that of LW during childhood. BSA would serve as a practical alternative to LW for scaling adult dosage of metabolically eliminated drugs to children.

じん肺患者におけるテオフィリンの投与量と血中濃度に関する検討 各種体内動態変動要因の現れ方の差に関して

We investigated the appearance of various factors causing fluctuations in the metabolic fate of theophylline (TP) in pneumoconiosis outpatients. Concurrent drug use, congestive heart failure, and smoking were found to be fluctuation factors. There were 4 patient groups, 3 with one of these factors each and a control group with none of the factors. We investigated the correlations between the TP dose and the serum concentration and between age and the serum concentration/dose (C/D) ratio in these 4 groups. The relationships between the dose and serum concentration were as follows : control group : Y=1.377X (p<0.0001), concurrent drug use group : Y=1.408X (p<0.0001), congestive heart failure group : Y=1.695X (p<0.0001), and smoking group : Y=1.025X (p=0.0002). Linearity was obtained for each, and a significant difference (p<0.05) in the regression line was only seen between the congestive heart failure and smoking groups. In addition, compared with the control group, the serum concentration tended to rise when receiving a high dose in the congestive heart failure group. No significant correlation was found between age and the C/D ratio in any of the groups, but the C/D ratio was lower in the smoking group than in any of the 3 other groups (p<0.05). The above results suggest that when administering TP to pneumoconiosis patients one should pay special attention to fluctuation factors in order to decrease the TP clearance (TPCL) due to congestive heart failure when administering high doses of drugs, in patients with an increased TPCL due to smoking.

Effect of passive smoking on theophylline clearance in children.

The author investigated the effects of passive tobacco smoking on the metabolism of theophylline in a pediatric population. In a retrospective analysis of 201 children admitted to a pediatric unit for asthma, 31 were identified with an acute exacerbation of asthma of noninfectious origin in which environmental exposure to tobacco smoke could be established. The parents were known smokers with a minimum 1-pack-per-day habit. An age-and gender-matched control population of children was then identified who had an acute exacerbation of asthma without any environmental exposure to tobacco smoke. In addition, the patients in both groups received the same dose of intravenous aminophylline for a minimum of 48 hours to ensure steady-state conditions. Total body clearance of theophylline was significantly elevated in the children exposed to environmental tobacco smoke (1.36 +/- 0.09 vs. 0.90 +/- 0.04 mL/min per kg, p < 0.0001). Steady-state serum levels were significantly lower in the passive smoking group (55.3 +/- 2.8 vs. 73.2 +/- 3.3 p < 0.00001) for those receiving nearly identical intravenous doses. The length of hospital stay was longer in the group exposed to passive smoke (4.4 +/- 2.6 vs. 2.9 +/- 1.3 days, p < 0.05). The clearance of theophylline is greater in asthmatic children exposed to passive tobacco smoke than in asthmatic children not exposed to passive tobacco smoke. These findings suggest that passive smoking may increase the clearance of other drugs metabolized in a manner similar to theophylline.

Tegaserod Coadministration Does Not Alter the Pharmacokinetics of Theophylline in Healthy Subjects

Tegaserod (HTF 919), a selective 5‐HT4 receptor partial agonist, is in development for the treatment of functional gastrointestinal motility disorders. Tegaserod has been found to inhibit cytochrome P‐450 (CYP) 1A2, for which theophylline is a prototype substrate. This study was designed to assess the effect of tegaserod on the single‐dose pharmacokinetic and safety profile of theophylline. Eighteen subjects were enrolled in a randomized, open‐label, two‐period crossover study. After an overnight fast, subjects were randomized to receive one of two treatments: (1) a single dose of controlled‐release formulation of theophylline (Theo‐Dur®, 600 mg) on day 1 or (2) a single dose of tegaserod (6 mg) on day 1, concomitant administration of tegaserod (6 mg) and theophylline (600 mg) on the morning of day 2, followed by an additional dose of tegaserod (6 mg) 12 hours later. Four to 10 days later, the subjects received the alternative treatment regimen. The pharmacokinetic parameters of theophylline, including AUC, Cmax' and t1/2Λz' were similar for both treatment regimens, although the tmax of theophylline was statistically different between the treatments. Except for a decrease in partial metabolic formation clearance from theophylline to 1‐methyluric acid, which is unlikely to be clinically relevant, there were no statistically significant differences in renal clearance of theophylline and partial metabolic formation clearances following the combined treatment compared with theophylline alone. The results of the current study indicate that no dose adjustment is required when drugs metabolized via CYP1A2 are coadministered with tegaserod.

Alteration of Drug Kinetics in Rats following Exposure to Trichloroethylene

The effect of trichloroethylene (TCY) was investigated to determine whether repeated exposure alters the pharmacokinetics of some drugs. Sprague-Dawley rats were given intraperitoneal injections of TCY (5 mmol/kg) in corn oil once daily for 3 days, while the control group received only corn oil. Four hours after the last dose, theophylline, quinidine, or pentobarbital were administered. Blood samples were collected at appropriate intervals for drug analyses. There was a small decrease in plasma clearance of theophylline, with no change in volume of distribution (V_d) as compared with controls. For quinidine, the elimination half-life was unchanged, and the V_d was decreased by 40%. The clearance of pentobarbital was decreased by 40% in male rats, but not in the females. Nonetheless, the duration of the sleeping time for both sexes was remarkably prolonged as compared with the control group. There was a decrease in the cytochrome P-450 content only in male rats. In conclusion, exposure to TCY causes changes in some drug kinetics, probably resulting from differential effects on the drug-metabolizing enzymes.

Effect of Levofloxacin on Theophylline Clearance During Theophylline and Clarithromycin Combination Therapy

OBJECTIVE:To report a case of decreased theophylline clearance by the addition of levofloxacin in a patient receiving theophylline and clarithromycin.CASE SUMMARY:A 59-year-old Japanese man who was receiving theophylline for emphysema experienced stimulation, insomnia, and tachycardia due to theophylline toxicity after clarithromycin and levofloxacin were added to the regimen. The combination of these agents resulted in a decrease in theophylline clearance to approximately 60% of the initial value obtained while the patient was receiving theophylline alone. The adverse effects disappeared after the dosage was reduced and the theophylline serum concentration decreased; however, there was no change in theophylline clearance. After discontinuation of levofloxacin, the theophylline serum concentration decreased, and theophylline clearance returned to the initial level even though clarithromycin was continued.DISCUSSION:Levofloxacin is believed not to influence the clearance of theophylline, although some new fluoroquinolones have been reported to do so. This case indicates that levofloxacin and clarithromycin inhibited theophylline metabolic pathways catalyzed by both CYP1A2 and CYP3A4 and resulted in the decrease in theophylline clearance. The clearance of theophylline, therefore, is not influenced by clarithromycin alone.CONCLUSIONS:Careful monitoring is required when levofloxacin is prescribed for patients who are taking clarithromycin with theophylline.

Ｔｈｅｏｐｈｙｌｌｉｎｅの薬物相互作用の母集団薬物動態解析

Selecting the optimum dose of theophylline is difficult because of the complication of pharmacokinetics caused by inter-individual variability and the effects of coadministration with other drugs.The steady-state serum concentration of theophylline (n=221) following repetitive oral administration in 174 hospitalized patients was analyzed using NONMEM. Analysis of the pharmacokinetics of theophylline was accomplished with a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of theophylline were investigated. The clearance of theophylline was significantly influenced by the demographic variables of age, and co-administration with ciprofloxacine or allopurinol. Estimates obtained by NONMEM indicated that the clearance of theophylline in patients under 16 years old was 128% higher than that in those over 16 years old.Concomitant administration of ciprofloxacine or allopurinol decreased the clearance of theophylline by 56.3% and 69.4%, respectively.The final regression model of relative clearance of theophylline was: CL (ml/kg/h) =40.5ξ×5ξ×6ξ×7where ξ5=0.563 for co-administration of ciprofloxacine, ξ6=0.694 for co-administration of allopurinol, ξ7=1.28 for patients younger than 16 years old.This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent of drug interaction.

The impact of acute phase response on the plasma clearance of antipyrine, theophylline, phenytoin and nifedipine in rabbits.

The impact of acute phase response (APR) on the plasma clearances of antipyrine, theophylline, phenytoin and nifedipine was studied using 50 female rabbits. APR was induced by a bolus intramuscular injection of Escherichia coli lipopolysaccharide (LPS, 50 microg/kg). No abnormal findings, other than an increase in rectal body temperature and the plasma concentration of interleukin-6 (IL-6), were observed in the LPS-treated animals. Twenty-four hours after LPS injection, the pharmacokinetic parameters of the four drugs were obtained following intravenous administrations of antipyrine (7 mg/kg), theophylline (5 mg/kg), phenytoin (10 mg/kg) and nifedipine (1 mg/kg). Total body clearances of antipyrine, theophylline, phenytoin and nifedipine in LPS-treated rabbits decreased, and terminal elimination half-life and the mean residence time of these drugs increased compared with those in the control rabbits. The apparent volume of distribution for phenytoin and nifedipine increased after the LPS injection, although the binding percentage of the drugs with plasma protein did not change. These results suggested that APR appears to decrease the plasma clearances of these drugs in rabbits, which may be due to the suppression of the activity of cytochrome P450 enzymes.

Effect of disease states on theophylline serum concentrations: are we still vigilant?

The use of theophylline has decreased over the past decade because of concerns over the risks of serious adverse effects as well as availability of more effective, safer drugs. Because of this decline in use, some clinicians may not be alert to the marked effect of some disease states on theophylline serum concentrations. The purpose of this review is to heighten awareness of the effect of decompensated heart failure, cor pulmonale, hepatic dysfunction, thyroid disease, and febrile illness on theophylline serum concentrations. Because many patients receive some benefit from this drug, safe use by clinicians requires closer monitoring of serum concentrations in patients with factors that alter theophylline clearance, including several disease states.

Effect of Disease States on Theophylline Serum Concentrations: Are We Still Vigilant?

The use of theophylline has decreased over the past decade because of concerns over the risks of serious adverse effects as well as availability of more effective, safer drugs. Because of this decline in use, some clinicians may not be alert to the marked effect of some disease states on theophylline serum concentrations. The purpose of this review is to heighten awareness of the effect of decompensated heart failure, cor pulmonale, hepatic dysfunction, thyroid disease, and febrile illness on theophylline serum concentrations. Because many patients receive some benefit from this drug, safe use by clinicians requires closer monitoring of serum concentrations in patients with factors that alter theophylline clearance, including several disease states.

シメチジンの用量と薬物相互作用発現の関係 文献調査ならびにテオフィリン体内動態の変動

Cimetidine (CIM), a histamine H2-receptor antagonist, has been demonstrated to reduce the clearance (CL) of a number of drugs. Up to date, 29 drugs, whose CLs are reduced by the coadministration of CIM, are listed under their package insert. We reviewed the original articles investigating the potential drug interaction between CIM and these drugs, and analyzed the relationship between the daily dosage of CIM and the alteration of the CL of the coadministered drugs.The decrease in the CL in the coadministration of CIM varied greatly from chlordiazepoxide with the largest decrease (56.7%) to mexiletine with the smallest (6.0%). The dose of the CIM described in original articles also varied greatly with the largest dose 2, 400 mg/day and the lowest 300 mg/day. A dose of over 800 mg/day of CIM, which is the upper limit of the usual dose in Japan, comprised 98% of all reported cases. A 1, 200 mg/day dose (16.6 mg/kg/day) of CIM, which was the most frequent dose described in the literature, was 2.5 times higher than the 400 mg/day dose (6.7 mg/kg/day) which is the usual dose in recent years in our country.The CL and serum trough concentration of theophylline (TP) were measured before and after the oral coadministration with a dosage of 400 mg/day or 800 mg/day of CIM for 5 days in four healthy subjects. The alteration in the serum trough concentration (about a 35% increase) and the CL (about 20% decrease) of TP induced by the coadministration of 800 mg/day of CIM, was much greater than that observed after the coadministration at 400 mg/day.These results suggest that the uniform change in prescriptions only based on the names of the drugs used in combination must be reexamined, and that it is necessary to improve the drug interaction-check system based on scientific evidence. after carefully evaluating the dose of the drug used.

Safety of the New Fluoroquinolones Compared with Ciprofloxacin

SummarySignificant safety issues that have arisen with fluoroquinolones include phototoxicity, cardiotoxicity, tendinitis, CNS effects and drug interactions. Ciprofloxacin is well tolerated; the incidence of adverse events is low and serious adverse events are rare. Levofloxacin has a reduced CNS adverse event rate compared with ofloxacin. Sparfloxacin has significant phototoxicity and potential cardiac toxicity. Grepafloxacin has significantly increased adverse event rates, particularly gastrointestinal intolerance. Taste perversion and nausea are common. Trovafloxacin has an increased potential for CNS adverse reactions, notably dizziness. Post-marketing surveillance data indicate the possibility of serious hepatic reactions and pancreatitis.Interactions between fluoroquinolones and drugs metabolised by the hepatic cytochrome P450 system affect the clearance of theophylline and caffeine. Quinolone absorption is significantly reduced by co-administration of antacids.Hospitalised patients are likely to be receiving multiple-drug therapy, but drug interactions are avoidable. The interactions of specific fluoroquinolones should be checked prior to prescription.

Comparative effects of oxygen supplementation on theophylline and acetaminophen clearance in human cirrhosis

Background & Aims: Sinusoidal capillarization in cirrhosis may impair the transfer of oxygen into hepatocytes; this may contribute to impaired oxidative drug metabolism. The aim of this study was to test this hypothesis by comparing the effects of oxygen supplementation in cirrhotic patients on the clearance of theophylline, which is dependent on hepatic oxidative metabolism, with its effect on the clearance of acetaminophen, which is reliant on hepatic conjugation reactions. Methods: Ten cirrhotic patients awaiting liver transplant and 5 control subjects were studied. Oral acetaminophen (1000 mg) and intravenous theophylline (3 mg/kg) were administered simultaneously on two separate occasions, 7 days apart. Subjects were randomized to breathe either room air or oxygen via face mask at 12 L/min for 9 hours of blood sampling. Results: Theophylline and acetaminophen clearances were significantly reduced by a mean of 54% and 50%, respectively, in cirrhotic patients compared with controls. Oxygen supplementation improved plasma theophylline clearance in cirrhotic patients by a mean of 34% ( P = 0.001), whereas acetaminophen clearance remained unchanged. Conclusions: These findings indicate that, in cirrhosis, impaired hepatocyte oxygenation contributes to reduced oxidative drug metabolism and that oxidative drug metabolism can be improved by oxygen supplementation. GASTROENTEROLOGY 1999;116:915-920

Biotransformation of theophylline in cirrhotic rats induced by biliary obstruction.

The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by biliary obstruction when aminophylline (8 mg/kg as theophylline, i.v.) was administered. 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 and the changes in the activity of drug metabolizing enzymes, which are suggested to be involved in theophylline metabolism, were determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to 30% of the control value while AUC (area under the plasma concentration-time curve) and (t1/2)beta were increased 1.3 fold and 3.5 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to 30% of the control value in microsomes of cirrhotic rat liver. In cirrhotic rat liver, activities of aniline hydroxylase (CYP2E1 related), erythromycin-N-demethylase (CYP3A related), and methoxyresorufin-O-demethylase (CYP1A2 related), which were reported to be related with theophylline metabolism, were decreased to 67%, 53%, and 76% that of normal rat liver, respectively. From the results, it can be concluded that in cirrhotic rats induced by biliary obstruction, the total body clearance of theophylline is markedly reduced and it may be due to decreased activity of drug metabolizing enzymes in liver.

Theophylline for chronic symptomatic bradycardia in the elderly.

The treatment of choice for chronic, symptomatic bradycardia is the placement of a cardiac pacemaker. Individuals who refuse or cannot tolerate pacemaker insertion usually require pharmacologic therapy. Hydralazine, prazosin, anticholinergics, and sympathomimetic agents have been administered for this indication, but adverse effects and limited data hinder routine, long-term use. Theophylline has emerged as a reasonable alternative strategy. For the medical management of bradycardia in the elderly, the literature supports theophylline dosages between 400 and 600 mg/d (approximately 8 mg/kg/d) administered in divided doses. This dosage range should result in a steady-state serum concentration between 5 and 15 mg/L. While some investigators recommend potentially higher initial doses (up to 12 mg/kg/d), lower dosages are more appropriate in the elderly due to decreased theophylline clearance. Initial dosage titration may be indicated and prolonged therapy is expected on the basis of the common etiologies of bradycardia in this patient group. Patient specifics such as altered theophylline metabolism (e.g., smoking), drug interactions (e.g., ciprofloxacin), and concomitant disease states (e.g., hepatic disease, heart failure) should always be considered in theophylline dosage recommendations. Clinicians should adjust the theophylline dose on the basis of patient response, including heart rate and clinical symptomatology, as well as measurement of occasional theophylline concentrations, if deemed appropriate. Theophylline should be avoided in the bradycardia-tachycardia manifestations of sick sinus syndrome or when ventricular ectopy is frequent. Additional investigation will further define the role of theophylline in elderly patients with chronic, symptomatic bradycardia.

Discussion

The induction of a number of drug-metabolizing enzymes is among the best-understood biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related agonists of the aryl hydrocarbon receptor (AhR). Among the cytochrome P450s (CYPs), the genes encoding CYP1A1, 1A2, and 1B1 are responsive to AhR agonists, i.e. their expression is inducible in various mammalian tissues and organs as well as in many types of cell lines and primary cells in culture. In addition, an aldehyde dehydrogenase, an NADPH-quinone-oxidoreductase, and the phase II conjugating enzymes glutathione-S-transferase (GST) Ya and UDP-glucuronosyltransferase 1A1 have been identified as responsive to AhR agonists. Induced expression of these members of the AhR gene battery is thought to be aimed at an improved elimination of the inducing agent and its metabolites. However, the identity of the physiological ligand(s) of the AhR is still obscure. The consequences of induced expression of AhR-regulated genes encoding drug-metabolizing enzymes have been investigated in human populations, e.g. in smokers, and in various experimental models. A prominent example of increased adverse effects due to the induction of CYP1A isozymes is the metabolic activation of carcinogenic aromatic amines and polycyclic aromatic hydrocarbons. An increasing amount of data is also available on the impact of dioxin-type induction on the metabolism of drugs, food constituents, and endogenous substrates. For example, the hepatic clearance of the drug theophylline, which is widely used in asthma therapy, is enhanced significantly in smokers. Increased glucuronidation of thyroxine in rats treated with TCDD or other potent AhR agonists is thought to result in hypothyroxinemia and its biological consequences, such as sustained hyperplasia of the thyroid, bearing a higher risk of thyroid cancer. The relevance of these observations for humans exposed to dioxin-type inducers is discussed.

Effects of Erythromycin and New Macrolides on the Serum Theophylline Level and Clearance

BACKGROUND: Up to 90% of a theophylline dose is biotransformed, by interaction with one or more the variants of the cytochrome P-450 drug metabolism system. Macrolides affect the elimination of theophylline by influencing on the microsomal enzyme systems. We evaluate the effect of erythromycin and new macrolides on the serum theophylline level and clearance. METHOD: Subjects consisted of moderate asthmatic patients with normal renal and hepatic functions. All subjects were non-smokers and treated with oral theophylline 400mg per day. We randomly assigned 53 patients into four groups. Each group was treated with one macrolides, the first group erythromycin(n: 19, 500 mg bid), second roxitbromycin (n: 14. 150 mg bid), third clarithromycin (n: 10, 250 mg bid) and fourth azithromycin(n: 10, 250 mg bid). We measured the serum theophylline level and clearance at three intervals, at pretreatment, after the first and fourth week after receiving the following macrolides, erythromycin, roxithromycin and clarithromycin. When azithromycin was administered, the serum theophylline level was measured at pretreatment and after one week of treatment They were measured by a computerized program of Bayesian method. RESULTS: When compared with control, erytbromycin and roxithromycin-treated groups had a significantly elevated serum theophylline level and decreased clearance. However, there were no significant changes of the serum theophylline level and clearance in clarithromycin and azithromycin-treated groups. CONCLUSION: These results suggest that theophylline dose may need to be readjusted and have periodic drug monitoring when erythromycin or roxithromycin is administered concurrenfly.