Plasma Theophylline Clearance Research Articles

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.

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

Oxygen supplementation restores theophylline clearance to normal in cirrhotic rats

Background/Aims Capillarization associated with hepatic fibrosis may present a functional barrier to oxygen diffusion into the hepatocyte, and restriction on cellular oxygen supply may represent the rate-limiting constraint on hepatic oxidative drug metabolism. The aim of this study was to test this hypothesis by examining the effect of oxygen supplementation on plasma theophylline clearance in 10 control and 10 cirrhotic rats. Methods Theophylline (3 mg/kg) was administered intravenously on two separate occasions, 24 hours apart, during which time the rats breathed either room air or oxygen (95%) from 1 hour before dosing until the end of plasma sampling with a randomized order of gas exposure. Results Theophylline clearance was significantly reduced by a mean of 37% (n = 10; P = 0.003) in cirrhotic rats compared with controls. Oxygen supplementation significantly improved plasma theophylline clearance in cirrhotic rats by a mean of 40% (n = 10; P = 0.007), whereas clearance remained unchanged in healthy rats. Clearance in oxygen-supplemented cirrhotic rats was not significantly different from that in controls ( P > 0.05). Conclusions These novel findings indicate an important role for hepatic oxygenation in improving drug disposition in cirrhosis, which may have potentially important clinical implications for the management of this disease.

The effect of tocainide on theophylline metabolism.

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 +/- 6.9 (mean +/- s.d.) to 33.7 +/- 5.0 ml kg-1 h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 +/- 2.5 to 10.4 +/- 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1,3-dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.

Inhibition of theophylline metabolism by mexiletine in young male and female nonsmokers

The influence of mexiletine (200 mg every 8 hours) on theophylline metabolism was studied in young male (n = 7) and female (n = 8) nonsmokers. A single-dose study of theophylline kinetics was performed at baseline and after 5 days of mexiletine treatment. With mexiletine the plasma clearance of theophylline decreased from 33.5 +/- 2.6 (mean +/- SEM) to 17.9 +/- 1.0 ml/kg per hour in the female group (p less than 0.001) and from 32.3 +/- 2.6 to 19.3 +/- 1.3 ml/kg per hour in the male group (p less than 0.001). The elimination half-life was prolonged by 74% and 103% in the male and female groups, respectively. Mexiletine decreased the formation of all theophylline metabolites in both groups. Within each group, the demethylation pathways were affected more than the hydroxylation pathway. These data indicate that mexiletine is a potent inhibitor of theophylline metabolism. This effect is not influenced by gender. Concurrent administration of these drugs may require a dose reduction of theophylline by as much as 50% to minimize the risk of toxicity.

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.

THEOPHYLLINE PLASMA CLEARANCE IN CRITICALLY ILL GERIATRIC PATIENTS RECEIVING TOTAL PARENTERAL NUTRITION and IN CONTROL PATIENTS

Mean values and standard deviations are reported for theophylline plasma clearance in 45 hospitalized geriatric patients (age greater than 65 years), distributed into two groups: Group I (n = 24) included critically ill patients admitted to the ICU on total parenteral nutrition (TPN). Group II (n = 21) included patients admitted to the Internal Medicine Ward without TPN. All patients were treated with a constant intravenous infusion of aminophylline. Group I patients had a lower mean theophylline clearance of 0.42 +/- 0.23 ml/kg/min compared to Group II 0.64 +/- 0.24 ml/kg/min (P = 0.003).

Induction of Theophylline Metabolism by Pentobarbital

Summary: Theophylline concentrations in plasma and urine were determined during maintenance treatment in nine healthy volunteers during one dosage interval before and after 10 days of simultaneous treatment with pentobarbital (100 mg each night). During the pentobarbital period, total plasma clearance of theophylline increased by 40% (range −4-79%), whereas renal clearance remained unchanged. It is concluded that therapeutic doses of pentobarbital induce the metabolism of theophylline with marked interindividual variation.

Induction of Theophylline Metabolism by Pentobarbital

Theophylline concentrations in plasma and urine were determined during maintenance treatment in nine healthy volunteers during one dosage interval before and after 10 days of simultaneous treatment with pentobarbital (100 mg each night). During the pentobarbital period, total plasma clearance of theophylline increased by 40% (range -4-79%), whereas renal clearance remained unchanged. It is concluded that therapeutic doses of pentobarbital induce the metabolism of theophylline with marked interindividual variation.

Dose-dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics

The influence of disulfiram on theophylline metabolism was studied in 20 recovering alcoholics. Ten of the patients, who were selected at random, received 250 mg of disulfiram daily. The other 10 patients received 500 mg of disulfiram daily. Two single-dose studies of theophylline kinetics were performed--one as a baseline control and the other after 1 week of treatment with disulfiram. With disulfiram pretreatment, the plasma clearance of theophylline was decreased from 105.7 +/- 10.2 (mean +/- SEM) to 83.1 +/- 8.1 ml/kg per hour (p less than 0.001) in the 250 mg group and from 94.3 +/- 13.3 to 65.4 +/- 10.7 ml/mg per hour (p less than 0.001) in the 500 mg group. The elimination half-life was prolonged significantly in both groups. The percent reduction in theophylline clearance was greater in the 500 mg group (32.5 +/- 3.1; range, 21.6 to 49.6) than it was in the 250 mg group (21.2 +/- 1.7; range, 14.6 to 29.6; p less than 0.01). Disulfiram decreased the formation of all theophylline metabolites in smokers in both treatment groups. In each group, the hydroxylation pathway was affected more than the demethylation pathway. These data indicate that at therapeutic doses disulfiram exerts a dose-dependent inhibitory effect on theophylline metabolism. Depending on the dose of disulfiram, a dose reduction of theophylline by as much as 50% may be necessary to minimize the risk of toxicity.

Lack of effect of terfenadine on theophylline pharmacokinetics and metabolism in normal subjects.

The pharmacokinetics of oral theophylline (250 mg) and the production of its metabolites (3-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid) were studied before and after the administration of oral terfenadine (120 mg twice daily for 16 days) in 10 healthy volunteers. Comparison of volumes of distribution, elimination half-lives, areas under the plasma concentration-time curves, plasma clearance of theophylline and elimination of theophylline metabolites indicated that terfenadine had no significant effect on theophylline pharmacokinetics and metabolism.

The beagle dog as an animal model for a bioavailability study of controlled-release theophylline under the influence of food.

Beagle dogs were evaluated as an animal model to study the effect of food on the bioavailability of two commercially available oral controlled-release theophylline products. The products were administered with and without food in single doses, and the bioavailability parameters were compared with those following an i.v. aminophylline dose. The total plasma theophylline clearance in dogs following an i.v. dose was 0.128 liter/hr/kg and the volume of distribution was 0.8 liter/kg using a one-compartment model. The absolute bioavailabilities of these two products under fasting conditions were 31 and 48%, respectively. The food increased the bioavailability of one product and decreased the bioavailability of the other. The overall trends in relative bioavailability of these two products with and without food appeared to be similar to those reported in humans.

The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition.

Theophylline interacts pharmacokinetically with a variety of other drugs. Recently enoxacin was found to change theophylline's disposition. In a four-subject, four-way crossover study enoxacin was administered every 12 hours at four levels (0, 25, 100, and 400 mg) for 14 doses. With the ninth dose of enoxacin, 200 mg theophylline was coadministered. Blood and urine samples were assayed by sensitive and specific assays for the parent drugs and their metabolites. Significant reduction in the formation of theophylline's three major metabolites occurred on coadministration of enoxacin. At the 400 mg dose level, enoxacin caused a threefold decrease in theophylline's plasma clearance, a fourfold decrease in the urinary recovery of 3-methylxanthine and 1,3-dimethylurate, and a threefold decrease in the recovery of 1-methylurate.

Application of theophylline metabolite assays to the exploration of liver microsome oxidative function in man.

The effects on theophylline oxidative metabolism of 3 inhibitors of liver microsome activity--cimetidine, troleandomycin and ketoconazole--were investigated in 6 healthy volunteers. The 3 compounds increased plasma theophylline half-life by 73.6 +/- 15.6% (P less than 0.01), 107.8 +/- 9.7% (P less than 0.001) and 21.7 +/- 6.8% (P less than 0.02), respectively, and reduced plasma theophylline clearance by 38.3 +/- 4.8% (P less than 0.001), 51.4 +/- 2.4% (P less than 0.001), and 8.9 +/- 7.8% (NS), respectively. Troleandomycin inhibited to the same extent the 2 theophylline metabolism pathways: N-demethylation resulting in the formation of 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX), and 8-hydroxylation resulting in the formation of 1,3-dimethyluric acid (1,3-DMU). The production clearances of these metabolites were almost equally depressed by 60.2 +/- 3.9%, 60.2 +/- 2.1%, and 51.7 +/- 4.5%, respectively. Cimetidine predominantly inhibited the N-demethylation pathway; the production clearances of 1-MU and 3-MX were depressed by 58.5 +/- 4.0% and 57.5 +/- 4.1% (P less than 0.001), respectively, whereas the production clearance of 1,3-DMU was depressed by 38.3 +/- 6.1% (P less than 0.001). Ketoconazole had no significant effect on the produciton clearances of theophylline metabolites. Measurement of theophylline metabolite formation clearances might be a useful test to explore liver microsome oxidative function.

Determinants of free theophylline clearance in asthma.

1. The free and total plasma and saliva concentrations of theophylline were measured during a dosing interval at steady state in nineteen asthmatic subjects receiving a once-daily theophylline preparation (Riker TCR-1). 2. Saliva theophylline clearance (mean +/- s.d. 5.8 +/- 2.1l h-1) was closely related to total plasma theophylline clearance (mean 3.6 +/- 1.2l h-1) (r = 0.958, n = 19, P less than 0.001). 3. Saliva theophylline clearance was closely related (r = 0.967, n = 19, P less than 0.001) and numerically very similar to the free plasma theophylline clearance (mean 5.8 +/- 1.9l h-1) (mean difference = 0.06 +/- 0.12 s.e. mean). 4. Free plasma theophylline clearance was significantly, although weakly, related to body weight and to the plasma free thyroxine concentration which together accounted for over 40 per cent of the variability in free clearance. 5. Theophylline administered for 2 weeks did not affect plasma free thyroxine (FT4) free tri-iodothyronine (FT3) or reverse tri-iodothyronine (rT3) concentrations compared with placebo.

The interaction of erythromycin with theophylline.

We have studied the interaction of erythromycin with theophylline. We gave ten healthy volunteers theophylline as an intravenous loading dose (5 mg X kg-1) over 1 h, followed by a maintenance infusion (0.5 mg X kg-1 X h-1) for 5 h. A second infusion of theophylline was given after 9 days of treatment with 1 g erythromycin base daily, and the concentrations of theophylline were determined during the infusion periods. The concentrations of erythromycin were measured for 8 h, after one week of treatment, and also after the last erythromycin dose, simultaneously with the second theophylline infusion. Concentrations within the therapeutic range were obtained with both drugs. A significant increase in both AUC and mean plasma concentrations of theophylline was seen during erythromycin treatment. The plasma clearance of theophylline was reduced in 9 of the 10 subjects. Renal clearance increased correspondingly, but the change was not statistically significant. Serum concentrations of erythromycin fell significantly, by more than 30%, with concurrent theophylline medication. We conclude that an interaction between theophylline and erythromycin, affecting both drugs, can be shown with concentrations of the drugs within the therapeutic range.

Selectivity and dose-dependency of the inhibitory effect of propranolol on theophylline metabolism in man.

The effects of separate 5 day pretreatments of propranolol 120 mg day-1 and 720 mg day-1 on theophylline clearance and metabolism at steady-state were determined in seven healthy males. Propranolol 120 mg day-1 decreased theophylline plasma clearance (CL) by 30%. Clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylated products by 42-43% and clearance to the 8-hydroxylation product by 27%. Propranolol 720 mg day-1 decreased theophylline CL by 52%. Again, clearance of theophylline to each metabolite was reduced by this treatment, clearances to the two demethylation products by 73-77% and clearance to the 8-hydroxylation product by 44%. These data are consistent with a dose-dependent and selective inhibitory effect of propranolol on the separate forms of cytochrome P-450 involved in theophylline demethylation and 8-hydroxylation.

Cimetidine-methylprednisolone-theophylline metabolic interaction

The pharmacokinetics of theophylline and methylprednisolone were examined before and during cimetidine treatment in an asthmatic woman who required long-term administration of these drugs. Cimetidine reduced theophylline plasma clearance by 30 percent, and measurement of urinary metabolites showed that 3-methylxanthine formation was inhibited more strongly than that of the methylated uric acid metabolites. Assessment of methylprednisolone disposition following oral and intravenous doses revealed no effect of cimetidine on the bioavailability (74 to 81 percent absorption) or plasma clearance (22 to 24 liters per hour) of the steroid. Thus, cimetidine exhibits variable and selective effects on the biotransformation pathways of drugs important in asthma therapy.

Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways.

The effect of rifampicin pre-treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1-demethylation by (116 +/- 34%) (mean +/- s.e. mean), 3-demethylation by (91 +/- 16%) and 8-oxidation by (81 +/- 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P-450 are involved in theophylline metabolism, one mediating the N-demethylations and the other 8-oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P-450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences.

Severe theophylline toxicity: Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion

The presenting symptoms, course, and treatment of 10 patients with severe theophylline toxicity (heart rate above 120, multifocal atrial tachycardia or premature ventricular contractions, hypotension, seizures) are described. Theophylline levels at presentation averaged 66 μg/ml (range 30 to 180 μg/ml). All patients had marked tachycardia; 80 percent had gastrointestinal symptoms, 50 percent were hypotensive, and 20 percent had seizures. A known history of poor compliance or other risk factors to overdosage was present in 60 percent. Of the five patients in whom drug clearances were determined, two had uniform first-order drug elimination. Three had biphasic elimination with an initial period of delayed elimination due to either zero-order kinetics or continued drug absorption. During the first-order elimination period, mean plasma theophylline clearance was 28.0 ± 4.3 ml per minute with a half-life of 8.2 hours. In the patients with initially delayed elimination, the mean clearance during the slow phase was 9.6 ± 3.3 ml per minute with an apparent half-life of 31 hours. One patient was treated with charcoal hemoperfusipn but the others received conservative management alone; all recovered without permanent sequelae. Propranolol and verapamil were useful in controlling supraventricular tachycardia. It appears that most patients with severe theophylline toxicity can be managed without hemoperfusion, which should be considered only when drug clearance is reduced, and hypotension, tachycardia, ventricular ectopy, or seizures are refractory to conservative measures.