Study on transport of disopyramide into the intestinal lumen aimed at gastrointestinal dialysis by activated charcoal in rats

The characteristics of exsorption and/or excretion of disopyramide into the gastrointestinal lumen have been investigated after intravenous administration of the drug at doses of 10 and 30 mg kg-1 to rats by the in-situ single pass perfusion technique. Disopyramide was appreciably excreted into the bile where its levels were approximately ten-fold higher than those in the serum. The exsorption rate of disopyramide and mono-N-dealkyldisopyramide (MND) into the perfusate was increased with an increase in the serum level following an increase from 10 to 30 mg kg-1 in the dose of disopyramide. The average amounts of disopyramide exsorbed into the perfusate were 17.0 and 18.4% at the dose of 10 and 30 mg kg-1, respectively, whereas those of MND were less than 1% at both doses of disopyramide. Oral administration of activated charcoal reduced the serum disopyramide levels after intravenous administration of the drug (20 mg kg-1) compared with the control treatment. By oral administration of activated charcoal, t 1/2 and AUC were decreased to 89 and 82%, respectively, and Cltot was increased to 122% compared with the corresponding control treatment. Vd was not different between the treated rats and control rats. These results suggest that the oral administration of activated charcoal can enhance the clearance of disopyramide and MND from the blood.     

Comparison of intestinal and peritoneal dialysis of theophylline and phenobarbitone in rats

Intestinal dialysis of drugs by oral administration of activated charcoal has been compared with peritoneal dialysis in rats. The average amounts of theophylline transported over 120 min into the intestinal lumen and the peritoneal cavity were 15.7 and 16.5% of the intravenous dose (10 mg kg-1), respectively, showing no significant difference, whereas the amount of the same intravenous dose of phenobarbitone transported from the blood into the intestinal lumen (7.8%) was significantly smaller than that entering the peritoneal cavity (12.5%). The net water flux showed that secretion predominated in the peritoneal transport whilst absorption predominated in the intestinal transport for both drugs. However, the net water flux in the intestinal lumen after intravenous theophylline (as aminophylline) was significantly smaller than that following phenobarbitone. The differences in transport across the two membranes could be due to differences in the intrinsic properties of the could be due to differences in the intrinsic properties of the membranes, such as the surface area, the thickness of the membrane and the distribution of blood vessels. Differences could also be due to differences in the pharmacological effects of the drugs.     

Pharmacokinetic interactions between isoniazid and theophylline in rats.

Pharmacokinetic interactions between isoniazid and theophylline were studied in male Wistar rats, 206 +/- 17 g. Concomitant oral administration of 2 x 5 mg kg-1 isoniazid accelerated slightly the disposition of theophylline (10 mg kg-1, i.v.) whereas 2 x 25 mg kg-1 isoniazid slowed it marginally. The differences in distribution volume, systemic clearance and area under the concentration-time curve (AUC) between the high and the low dose, however, were statistically significant. One week pretreatment with 10 mg kg-1 isoniazid tended towards inhibition (significant decrease of systemic clearance, increase of AUC) and 50 mg kg-1 to acceleration (decrease of half-life, mean residence time and AUC, increase of systemic clearance) of theophylline disposition. After oral pretreatment with 20 mg kg-1 theophylline, neither the kinetics of free isoniazid (50 mg kg-1, i.v.) and the amount acetylated nor the acetylation indices differed from the controls. There was no evidence that concomitant or subacute administration of different doses of isoniazid affects major metabolic pathways of theophylline or that prolonged theophylline treatment interacts with the N-acetylation capacity.     

Dependence of the renal excretion of theophylline on its plasma concentrations and urine flow rate in asthmatic children

The dependence of the renal excretion of theophylline on its plasma concentration and urine flow rate has been investigated in asthmatic children of either sex. One group (age 12.25 +/- 0.80, mean +/- s.d. n = 8) was given aminophylline intravenously (i.v.), while another (age 10.00 +/- 3.64 n = 14) was given a sustained release preparation of theophylline orally (single dose and repeated doses). Unchanged drug (11.6% +/- 1.75) was excreted in the urine corresponding to a renal clearance of 10.6 +/- 1.6 mL h-1kg-1. Time dependence of the renal clearance of theophylline was found only after i.v. administration. Dependence of the renal clearance on urine flow rate was found both after i.v. administration and at steady state, but not after a single oral dose of theophylline. After oral administration, renal clearance of theophylline was higher at steady state than after a single dose (0.58 +/- 0.06 L h-1 kg-1 vs 0.23 +/- 0.03 L h-1 kg-1), while urine flow rate was lower (1.1 +/- 0.5 mL min-1 vs 1.8 +/- 0.9 mL min-1). High correlation of theophylline plasma concentration and theophylline excretion rate was obtained in 10 of 14 patients after administration of a single oral dose of the preparation (r = 0.8567 to 0.9830). There was no dose dependence of the renal clearance of the drug either after a single dose, or at steady state.     

Lack of effect of atenolol on the pharmacokinetics of theophylline.

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

The effects of atropine on pharmacokinetics of theophylline in rabbits.

The effects of atropine on serum concentrations and pharmacokinetics of theophylline were studied in six rabbits (2.07 +/- 0.11 kg). Theophylline serum concentration was determined by ultraviolet spectrophotometry. After i.v. administration of aminophylline 12.5 mg/kg, i.m. atropine 1 mg/kg decreased significantly the maximal serum concentration of theophylline from 23.6 +/- 1.1 to 19.6 +/- 1.1 mg/l, and increased that of theophylline at the time of 6 and 8 hours after injection. After i.v. aminophylline administration without or with atropine, the pharmacokinetic parameters of theophylline calculated using a one compartment open model were: K (elimination rate constant) = 0.23 +/- 0.03, 0.19 +/- 0.02/h; t1/2 (half life) = 3.04 +/- 0.40, 3.66 +/- 0.40 h; Cl (clearance) = 0.26 +/- 0.04, 0.23 +/- 0.03 l/kg/h, respectively (P less than 0.01). But there was no significant variation in modification of volume of distribution (Vd). The results suggested that there is a significant drug interaction between atropine and theophylline.     

Kinetics of Drug Action in Disease States. XXXIX. Effect of Orally Administered Activated Charcoal on the Hypnotic Activity of Phenobarbital and the Neurotoxicity of Theophylline Administered Intravenously to Rats with Renal Failure

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of pheno-barbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls. In the theophylline experiment, charcoal treatment had no significant effect on the measured biochemical variables but caused a large increase in the dose and concentrations of theophylline required to produce maximal seizures. In both experiments, administration of activated charcoal caused a reversal of the hyperalgesia associated with renal failure, as determined before drug administration by tail flick latency. These results are consistent with the hypothesis that oral administration of activated charcoal can cause a reduction in the concentration of the circulating endogenous substance(s) that alters the pharmacodynamics of certain drugs in renal failure.     

Comparative pharmacokinetics of theophylline and aminophylline in man.

1 The pharmacokinetics of theophylline and aminophylline was compared after oral administration and intravenous infusion. 2 Theophylline (250 mg) and aminophylline (390 mg) were taken orally by eight healthy volunteers in a randomized cross-over study. 3 In another cross-over study theophylline and aminophylline were administered intravenously to six healthy volunteers at a dose corresponding to 5 mg/kg pure theophylline. 4 The protein binding of the theophylline in serum collected during the intravenous study was studied by ultrafiltration. The serum concentration of theophylline was measured by high pressure liquid chromatography. 5 Almost identical concentration-time curves were found for theophylline and aminophylline in both of the studies. No significant difference was found in the pharmacokinetic parameters or protein binding with the two preparations.     

Kidney toxicity of 3-methylxanthine in the rat

The effects of 3-methylxanthine, the pharmacologically active metabolite of theophylline, on the kidneys of Wistar rats after short-term administration were studied. 3-Methylxanthine was administered in oral doses of 0 (control), 50, 100 and 200 mg per kg per day for 1, 8 and 16 days. The kidneys were examined by light and electron microscopy. Tubular necrosis was noticed at a dose level of 100 mg kg-1 after 16 days and at a dose level of 200 mg kg-1 after 8 days. Elevated values of serum urea were found after 1 day of treatment with a dose of 200 mg kg-1 and after 16 days with a dose of 100 mg kg-1. Elevated values of serum creatinine were detected after 8 days of treatment with a dose of 200 mg kg-1. The results indicate dose- and time-related renal failure following administration of 3-methylxanthine.     

Comparative effect of theophylline and aminophylline on theophylline blood concentrations and peripheral blood eosinophils in patients with asthma

The comparative effects of a new theophylline preparation (Theodrip) and aminophylline on blood concentrations of theophylline were examined in 74 patients with asthma. Subjects were intravenously administered 200 mg of Theodrip or 250 mg of aminophylline for 1 h. The mean increases in blood theophylline concentration after Theodrip or aminophylline administration were 8.80 +/- 1.80 mg/l and 8.81 +/- 2.15 mg/l, respectively. In addition, these patients were divided into four groups based on baseline theophylline concentrations before infusion of Theodrip or aminophylline: i) na?ve patients (not administered theophylline); ii) those with a baseline theophylline concentration of 0-5 mg/l; iii) those with a baseline theophylline concentration of 5-10 mg/l; iv) those with a baseline theophylline concentration of 10-15 mg/l. Mean increases in blood theophylline concentration after administration of Theodrip in each group were similar to those after aminophylline administration. We found no significant differences between Theodrip and aminophylline. However, when the comparative effects of Theodrip and aminophylline on peripheral blood eosinophil counts were examined, Theodrip, but not aminophylline, reduced blood eosinophil counts. With acute exacerbations of bronchial asthma, it is expected that Theodrip, but not aminophylline, may have an antiinflammatory effect. In conclusion, it is suggested that Theodrip is a more useful drug than aminophylline in patients with acute exacerbations of bronchial asthma.     

Studies on the mechanisms of action of activated charcoal on theophylline pharmacokinetics

Oral administration of repeated doses of activated charcoal to volunteers and dogs significantly increased the systemic clearance of intravenously administered theophylline and decreased its elimination half-life. This effect is most likely to be due to theophylline entering the gut and being adsorbed onto the charcoal. The mechanism by which intravenously administered theophylline enters the gut has been examined. Its biliary excretion after intravenous administration to patients with T-tube biliary drainage accounted for 0.28% of the dose and a similarly small biliary excretion was found in dogs. In the latter total biliary diversion had no effect on the clearance or half-life of theophylline after intravenous administration. In two dogs the theophylline content of jejunal aspirate was comparable with that of simultaneously withdrawn venous plasma samples. These results suggest that the presence of charcoal in the gut represents a sink adsorbing theophylline entering the lumen by diffusion across the intestinal wall, and by this mechanism it increases clearance of the drug even after intravenous administration.     

Effect of cigarette smoking on theophylline pharmacokinetics in rats.

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

Serum theophylline concentrations and pulmonary function tests after administration of two sustained-release formulations containing theophylline in patients affected by chronic obstructive lung disease

We compared serum theophylline concentrations in patients treated with one of two commercially available theophylline preparations: a sustained-release aminophylline and a sustained-release theophylline. Two comparable groups of 15 out-patients with stable, chronic obstructive lung diseases were studied: one group was given sustained-release aminophylline while the other took sustained-release theophylline. Both drugs were administered orally for 7 days at a daily dose, equivalent to 12 mg/kg in terms of anhydrous theophylline. Serum theophylline concentrations were always significantly lower after treatment with sustained-release aminophylline than after treatment with sustained-release theophylline, which latter frequently caused undesirable side-effects. Moreover, patients receiving sustained-release aminophylline always showed serum theophylline concentrations lower than 10 mcg/ml. Pulmonary function tests were unaffected by the administration of either drug. We conclude that sustained-release theophylline is more effective than sustained-release aminophylline in terms of induced serum theophylline concentrations. However neither drug was suitable for the treatment of patients with chronic obstructive lung disease without other concomitant therapy.     

Pharmacokinetics of theophylline in ten elderly patients

The two-compartment pharmacokinetics of theophylline in ten hospitalized elderly patients with apparently normal renal, hepatic and cardiopulmonary functions was investigated after intravenous administration of the drug. Nine patients suffered from slight hemiparesis and one from Parkinson's disease. Biological theophylline half-lives of 5.4--9.0 hours and plasma clearence values of 28--42 ml kg-1hr-1 were found. The apparent volumes of distribution during the beta-phase, Vdbeta, were 0.33--0.43 1 kg-1. It is concluded that a therapeutic concentration of about 10 microgram theophylline per ml serum could be established in the investigated group of elderly patients following an intravenous initial loading dose of 3.7 mg theophylline per kg followed by a continuous infusion of 0.35 mg per kg body weight per hour. In the therapeutic use of theophylline monitoring of the serum theophylline concentration is generally advised because of the elsewhere reported variability in the biological half-life of the compound.     

Pharmacokinetic modelling of the effect of activated charcoal on the intestinal secretion of theophylline, using the isolated vascularly perfused rat small intestine

The effect of activated charcoal administration on the secretion of theophylline from the blood into the intestinal lumen has been examined by use of the rat isolated vascularly perfused small intestine. A closed two compartment model was used to analyse the vascular and luminal concentration-time curves obtained. An equation was derived to calculate the time-dependent intestinal clearance. From control experiments it was concluded that theophylline is secreted by a diffusional transport system through the intestinal wall. The intestinal clearance declined rapidly with time as a result of the concomitant increase in luminal theophylline concentration. After 120 min a steady state between the vascular and luminal perfusate was established. Administration of activated charcoal in the lumen had a profound effect on the kinetics of the drug. The vascular steady state concentration was depressed dramatically. The theophylline clearance remained nearly constant with time, because the blood to lumen concentration gradient was maximized. The maximal value for the intestinal theophylline clearance was estimated to be 0.88 mL min-1 and it equalled the value for the intestinal blood flow at the absorptive site. By use of the concept of absorptive site blood flow, the maximal effect of charcoal on systemic theophylline clearance could be adequately predicted for rats, dogs and man. Activated charcoal administration is only useful to enhance the systemic clearance of drugs or toxicants if that clearance is of the same order of magnitude as the absorptive site blood flow or lower.     

The rise and fall of serum theophylline concentration: a comparison of sustained-release formulations in volunteers with rapid theophylline clearance.

The pharmacokinetics of four sustained-release formulations of theophylline have been examined after single doses (Nuelin SA, Phyllocontin, Slo-phyllin and Theo-Dur) and at steady-state (Phyllocontin, Theo-Dur) in six healthy adult volunteers, selected because they all eliminated theophylline rapidly after an intravenous dose of aminophylline. After a single dose of Theo-Dur, the peak concentration of theophylline was smaller and occurred later than after single doses of Nuelin SA, Phyllocontin and Slo-phyllin, suggesting that absorption occurs over a longer period. The systemic availability of theophylline was virtually complete after all four formulations. After repeated 12-hourly dosing to steady-state, and adjustment of dose to achieve trough concentrations of between 5 and 10 mg l-1 (28-55 mumol l-1), theophylline concentration fluctuated to a significantly greater extent within a dose interval when the subjects were taking Phyllocontin than when they were taking Theo-Dur.     

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.     

Effects of intravenous theophylline, aminophylline and ethylenediamine on antigen-induced bronchoconstriction in guinea pigs

The antiasthmatic effect of i.v. injection of theophylline was compared with that of aminophylline by using an antigen-induced bronchoconstriction model in sensitized guinea pigs. Both theophylline and aminophylline showed dose-dependent inhibition of antigen-induced bronchoconstriction. Statistically significant differences were observed at theophylline doses of 20 and 40 mg/kg and at aminophylline doses of 25 and 50 mg/kg. Thus, antiasthmatic effects of both drugs appeared to be similar. In addition, intravenous ethylenediamine did not influence either airflow in normal guinea pigs or bronchoconstriction induced by antigen at doses up to 30 mg/kg. In conclusion, the ethylenediamine in aminophylline may not influence the antiasthmatic action of theophylline, and the therapeutic effects of theophylline and aminophylline are suggested to be similar.     

Kinetics of theophylline clearance in gastrointestinal dialysis with charcoal

The pharmacokinetic response of theophylline following the oral administration of activated charcoal was investigated in rabbits. Rabbits were continuously infused with a theophylline solution at a rate of 2.12 mg/h. At the fourth hour of theophylline infusion, 20 g of activated charcoal was administered by intubation to the rabbit (n = 12). The concentration of theophylline in serum gradually decreased after the charcoal treatment. The magnitude of the change in theophylline concentration induced by charcoal varied among animals. By comparing the steady-state theophylline concentration in the control and treated animals, the total body clearance was found to increase from 94.4 +/- 7.5 to 210 +/- 27 mL/h/kg (mean +/- SE). The rate of change of theophylline concentration in serum following charcoal treatment was fitted with a simulation curve by assuming a stepwise increase in clearance immediately following the charcoal treatment. The results indicated that activated charcoal exerted its maximum effect in increasing theophylline clearance immediately after its administration.     

Toxicity of theophylline depends on plasma concentration by single and also repeated dosing in rats.

The purpose of this study was to evaluate the relationship between the in vivo toxicity and plasma concentration of theophylline. Theophylline was administered intravenously in single doses ( 50, 100, 150 and 200 mg kg(-1)once a day) or repeated doses (12.5, 25 and 90 mg kg(-1)/day for 28 days) in rats. Plasma concentrations of theophylline increased dose-dependently in both single and repeated doses, and there were no differences due to effects of 28-times repeated administration. Neither single dose at 50 mg kg(-1)nor repeated dose at 12.5 mg kg(-1)/day injections of theophylline showed toxic signs, in which plasma concentrations of theophylline were less than 110 and 22.5 microg ml(-1), respectively. Theophylline induced myocardial fibrosis in 25 mg kg(-1)/day and more treated groups: in which plasma concentrations of theophylline were more than 50 microg ml(-1). At doses of 100 mg kg(-1)(single) and 90 mg kg(-1)/day (repeated), theophylline caused tachypnea and excitement of movement. Each theophylline concentration in plasma was more than 194 microg ml(-1)in single 100 mg kg(-1)and 162 microg ml(-1)in repeated 90 mg kg(-1)/day injections, respectively. Death was observed at a dose of 200 mg kg(-1), in which the plasma concentration of theophylline was more than 264 microg ml(-1). Moreover, the recovery period from signs of toxic poisoning to normality in the 200 mg kg(-1)treated group was greater than that in the 150 mg kg(-1)and less treated groups. The results indicated that the in vivo toxicity of theophylline is highly dependent on plasma concentrations in rats which received single and also repeated doses of theophylline.