Effects of chlorpromazine on the disposition and beta-adrenergic blocking activity of propranolol in the dog

The effects of chlorpromazine (100 mg p.o., 2 hr before propranolol) on the disposition and beta-adrenergic blocking actions of both intravenous (6 mg) and oral (40 mg) propranolol were studied in the dog. Chlorpromazine pretreatment significantly reduced (69%) the oral clearance of propranolol, resulting in significant increases in propranolol bioavailability (159%), and in the total beta-adrenergic blocking activity (111%) after the oral dose. The increase in the total beta-adrenergic blocking activity of oral propranolol after chlorpromazine pretreatment was mostly due to an increased contribution from the parent compound; the apparent activity from active propranolol metabolites was not affected by chlorpromazine. Chlorpromazine pretreatment had no significant influence on the systemic clearance, elimination half-life, apparent volume of distribution, and plasma binding of propranolol, or on the apparent hepatic blood flow. After intravenous propranolol, chlorpromazine pretreatment had no effect on either the total amount of beta-adrenergic blocking activity or the amount of activity attributable to active metabolites. The decreased oral propranolol clearance by chlorpromazine was seen as a shift to the left in the propranolol dose vs. AUC relationship, eliminating the apparent nonlinear kinetic behavior of oral propranolol, and reducing the apparent oral threshold dose. Chlorpromazine's major, if not only, effect on propranolol disposition was to reduce the presystemic elimination of propranolol, possibly through inhibition of its metabolism via a pathway other than ring oxidation.     

Influence of food on the intravenous and oral dose kinetics of propranolol in the dog

The intravenous and oral dose kinetics of propranolol were studied in the dog both in a fasted state and immediately after a meal consisting of 100 g of cooked beef liver. Fifty Ci of³H-propranolol was administered intravenously simultaneously with a 40-mg oral dose of unlabeled propranolol. Plasma³H-propranolol was measured by specific extraction and liquid scintillation spectrometry, and unlabeled plasma propranolol was determined by gas chromatography-mass spectrometry. Feeding significantly reduced (25%) the elimination half-life and increased (52%) the systemic clearance of intravenous propranolol. The increase in the systemic clearance of propranolol after feeding was mostly due to an increase (60%) in apparent hepatic blood flow, which appeared to remain elevated for 5–7 hr. The meal had no influence on the apparent volume of distribution or plasma binding. Feeding did not affect the area under the concentration-time curve of oral propranolol, but significantly delayed the rate of oral propranolol absorption, shifting the time to reach peak plasma levels from 60 to 158 min. The results of this study suggest that feeding alters the disposition of propranolol in the dog by producing a sustained increase in hepatic blood flow.This work was supported by National Institute of Health grants GM 07534, GM 20387, and HL 29566.     

The effect of chlorpromazine, metyrapone, imipramine and SKF 525-A on the hepatic first pass elimination of propranolol in the pithed rat.

1 The effect of chlorpromazine, metyrapone, imipramine and SKF 525-A on the hepatic first pass elimination of propranolol has been studied in the pithed rat. 2 The effect of chlorpromazine, metyrapone, imipramine and SKF 525-A on the inhibition caused by propranolol of an elicited electrically induced tachycardia has also been studied. 3 The hepatic first pass elimination of propranolol was reduced following pretreatment with chlorpromazine, imipramine and SKF 525-A but was not affected by pretreatment with metyrapone. 4 Chlorpromazine, imipramine and SKF 525-A all resulted in an increased propranolol blood concentration after hepatic portal vein administration which was associated with decreased formation of metabolites and an enhanced inhibition of an electrically induced tachycardia.     

Pharmacological blockade of amphetamine effects in amphetamine dependent subjects

Summary Pharmacological blockade of the euphoric effect of amphetamine was studied in amphetamine dependent patients. An eleven grade self-rating scale was used for registration of the subjective feeling of euphoria after intravenous administration of 200 mg d,l-amphetamine. Three neuroleptic drugs, chlorpromazine, thioridazine, pimozide, the -receptor-blocking agent phenoxybenzamine and the -receptor-blocking agent propranolol were tested for possible anti-amphetamine effect. — The euphoric effect of amphetamine was significantly reduced after a single dose of 50 mg of chlorpromazine and after 7 and 13 days of chlorpromazine treatment, 50 mg every 8 h. Single doses of chlorpromazine 25 mg or thioridazine 25 and 50 mg, respectively, had no effect. Pimozide significantly reduced euphoria after single doses of 5, 10 and 20 mg, but there was no dose-response relationship. The amphetamine-induced euphoria was also reduced by 7 and 13 days of treatment with pimozide 5 mg daily. Pretreatment for 6 days with phenoxybenzamine had no effect on the response to amphetamine and, propranolol, too both in single doses and after 5 days administration also had no amphetamine blocking effect. — Blood pressure, pulse rate, respiratory rate and body temperature were measured after administration of amphetamine before and after pretreatment with these blocking agents.Amphetamine significantly increased the blood pressure and at certain times the pulse and respiratory rates, too, but not the body temperature. If these blocking agents were given in combination with amphetamine they showed no particular effects on these parameters.     

Beta-adrenergic blocking activity and haemodynamic effects in man of Kö 1313, a new beta-adrenergic antagonist

Summary The beta-adrenergic blocking activity and haemodynamic effects of o-[2-hydroxy-3-(isopropylamino)-propoxy]-benzonitril (Kö 1313) have been studied in 22 patients. Antagonism of isoproterenol-induced tachycardia was used as a measure of the beta-adrenergic blocking activity. Kö 1313 1.0 mg had its maximum beta-adrenoceptor blocking effect 5–30 min after intravenous injection. Kö 1313 10.0 mg produced maximum betablockade 1–4 h after oral administration. 1.0 mg Kö 1313 injected intravenously had approximately the same beta-adrenergic blocking effect as 1.0 mg propranolol also given intravenously. After intravenous administration Kö 1313 was 3–4 times as potent as the same dose given orally. An intravenous dose of 2.0 mg Kö 1313 reduced the heart rate and produced insignificant fall in cardiac output. Total peripheral resistance was increased by Kö 1313.A preliminary account of this work has already been published (H. J. Gilfrich und K. H. Rahn, Verhandlungen der Deutschen Gesellschaft für Innere Medizin76, 925 (1970)).     

Single-dose kinetics of oral propranolol, metoprolol, atenolol, and sotalol: relation to lipophilicity

Nine healthy volunteers received single oral doses of the following four beta-adrenergic blocking agents: propranolol (160 mg), metoprolol (100 mg), atenolol (200 mg), and sotalol (320 mg). The kinetics of each drug were determined from multiple serum concentrations measured during 24-48 h after each dose, and in vitro lipid solubility determined using the liquid chromatographic (HPLC) retention index. Oral clearance for the four drugs ranged from 40.2 ml/min/kg for propranolol down to 2.1 for sotalol. Oral clearance was highly correlated (r = 0.99) with in vitro lipid solubility, with propranolol being the most lipophilic drug and sotalol the least. Thus lipophilicity is a physicochemical property of beta-adrenergic blockers that appears to influence their intrinsic clearance after oral dosage.     

The effect of ranitidine on the disposition of lignocaine.

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady-state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.     

Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H₂ -blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal® (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC_0–,values (573.5 vs. 146.4 ng·hr/ml, p=0.0001)and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropanolol indicates that etintidine also increased the AUC_0–24 values (43.8 vs. 16.4 ng·hr/ml, p=0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

Human pharmacokinetics of tolfenamic acid,a new anti-inflammatory agent

Summary The pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent was studied in six healthy volunteers after an intravenous dose of 100 mg and oral doses of 100, 200, 400 and 800 mg. The disposition of intravenous tolfenamic acid could be described by two-compartment open model, with a central compartment volume (V_dc) of 5.6±0.31 (mean±SE), volume during -phase (V_d) of 31±21, and a total elimination rate constant (k₁₀) 1.6±0.1 h^–1. The terminal elimination half-life was 2.5±0.6 h and the total plasma clearance 155±15 ml/min. The elimination occured principally by extrarenal mechanisms, the recovery of unchanged drug together with is glucuronide in urine averaging only 8.8% of the intravenous dose. The binding of tolfenamic acid to plasma proteins averaged 99.7%. The gastrointestinal absorption had a mean half-life of 1.7±0.1 h. Based on comparison of areas under the plasma concentration time-curves after intravenous and oral administration, the biovailability of tolfenamic acid capsules averaged 60%. The rate and extent of absorption and the rate of elimination of tolfenamic acid were independent of dose.     

Metabolism of atenolol in man.

1. The disposition and metabolism of 1-(4-carbamoyl[14C]methylphenoxy)-3-isopropylaminopan-2-ol (atenolol, Tenormin) has been studied in man following oral and intravenous doses. 2. Approx. 50% of an oral dose was eliminated in urine; the major radiolabelled component was atenolol (approx. 90%). Faecal extracts also contained largely unchanged atenolol, with small amounts of more polar metabolites. Biliary excretion of atenolol and its metabolites is not a major route of elimination in man. Metabolism of the compound is not extensive and route-dependent modes of metabolism do not appear to complicate the position. 3. Atenolol appeared to be the only major radiolabelled component in blood. 4. Oral doses of atenolol are incompletely absorbed (range 46-62%), even when formulated as a solution. 5. 1-[4-(C-Carbamoylhydroxymethyl)phenoxy]-3-isopropylaminopropan-2-ol was a minor urinary metabolite, which has only one tenth the activity of the parent compound as a beta-adrenergic blocking agent in the rat. 6. Pharmacological activity in man appears to be due to atenolol alone.     

Hemodialysis clearance of encainide and metabolites.

The disposition of encainide and metabolites O-desmethylencainide (ODE) and 3-methyl-ODE (MODE) was evaluated in a 31-year-old hemodialysis patient following a 25 mg oral dose during an interdialytic period and a second 25 mg oral dose 48 h later, 2 h before a hemodialysis procedure. The inter- and intradialytic elimination half-lives were not different for encainide and its metabolites ODE and MODE. The hemodialysis clearance of encainide, MODE, and ODE are all less than 10% of the creatinine clearance of the dialyzer. Thus, hemodialysis does not result in clinically significant removal of encainide or its metabolites.     

Pharmacokinetics of sulphinpyrazone and its major metabolites after a single dose and during chronic treatment

Summary The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t_1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t_1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.Abbreviations k_a first order rate constant for absorption or appearance - k_el first order rate constant for elimination - F extent of bioavailability - D administered dose (as free base) - k₁₂ first order distribution rate constant into peripheral compartment - k₂₁ first order distribution rate constant from peripheral compartment - k₁₀ first order elimination rate constant from central compartment - first order elimination rate constant of rapid disposition phase - first order elimination rate constant of slow disposition phase - V_z apparent volume of distribution - V_c apparent volume of distribution of central compartment - t time after drug administration - t_o lag time for absorption - Cp_(t) concentration in plasma at time t - n number of doses - Cp_(tn) concentration in plasma at time t after n^th dose - dose interval - CL clearance uncorrected for bioavailability F     

Pharmacokinetics of unlabelled and14C-labelled pindolol in uraemia

Summary The elimination of pindolol in 25 patients with various degrees of renal failure has been studied after an intravenous dose of 3 mg. A linear correlation was not found between the elimination rate of pindolol and the endogenous creatinine clearance, and the half-life of the unchanged drug was independent of the severity of the renal failure. This implies greater metabolism of pindolol in anuric patients and the extrarenal elimination rate constantk _mwas increased. Three patients with severe renal failure were given 3 mg¹⁴C-pindolol. They showed almost constant plasma levels of radio-activity for 6 h and then slow excretion with a half-life of 48 h, because of accumulation of metabolites in the blood. Up to 90% of the metabolites are glucuronides and sulphates which have no beta-blocking or other clinical activity. Thus, to produce beta-adrenergic blockade the same dose of indolol is required in healthy patients as in those with uraemia.     

Evidence that cannabidiol does not significantly alter the pharmacokinetics of tetrahydrocannabinol in man

The pharmacokinetics of ⁹ -tetrahydrocannabinol (THC) administered intravenously was evaluated in four subjects after oral administration of placebo and 1500 mg of cannabidiol (CBD) according to a crossover design. The cannabidiol pretreatment had no apparent effect on THC pharmacokinetics, yet there may have been minimal effect on the formation and excretion of metabolites. The total (metabolic) blood clearance of THC averaged 17.4 ml/min/kg without CBD and 20.9 ml/min/kg with CBD, and was probably hepatic blood flow limited. The apparent steady-state volume of distribution averaged 9.86 (with CBD, 10.54) liters/kg. Irrespective of CBD pretreatment, the renal clearance of THC metabolites ranged from 17 ml/min after approximately 1 hr to 1.13 ml/min 3.5days after dosing with THC. The apparent terminal half life for metabolites averaged 8.2 days.This work was supported by National Institute on Drug Abuse Grant DA-01773, Program Project Grant DA-01696 and Contract No. HSM-42-73-181.Recipient of National Institute on Drug Abuse Research Scientist Award DA-00053.     

Absorption,metabolism and elimination of strophanthus glycosides in man

Summary In 33 healthy male volunteers, given a single oral and intravenous dose of cymarin (k-strophanthin-), k-strophanthoside (k-strophanthin-) and ouabain (g-strophanthin), enteral absorption and renal excretion of these glycosides and their metabolites were investigated by radioimmunoassay and HPLC. Cymarin was absorbed at 47% of the given dose. After intravenous injection 46% and after oral administration 21% of the given dose, i.e. the total amount as detected by radioimmunoassay which consisted of the unchanged glycoside and its metabolites, were excreted by the kidneys mainly as conjugated metabolites. The half-life of elimination, calculated from the total excreted amount was 13 h (i.v.) and 23 h (p.o.), respectively. k-Strophanthoside was absorbed at 16% of the given dose. After i.v.-injection 73% of the given dose was excreted by the kidneys with a half-life of elimination of 99 h. From this total amount about 70% was excreted as the unchanged drug, the remaining 30% as various metabolites. After oral administration 11% of the given dose were excreted with a half-life of elimination of 22 h. 80% of this amount consisted mainly of conjugated k-strophanthoside and conjugated metabolites as k-strophanthin-, cymarin, k-strophanthidin, cymarol and k-strophanthidol. Only 6% was excreted as the unchanged drug. Ouabain was absorbed after oral administration to a minimum of 1.4%. Given intravenously a total renal excretion of 33% of the given dose with a half-life of elimination of 23 h was measured. Of this 80% was unchanged ouabain. The remaining 20% seemed to be conjugated metabolites which could not be exactly identified.Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich Düsseldorf (SFB 30)     

In vivo study of propranolol and metabolite(s) disposition in rat liver

To investigate the intrahepatic disposition of drugs subjected to the first-pass effect, propranolol (0.002 mg/kg and 5 mg/kg) was injected into the portal vein of rats. At various times the drug was measured in liver homogenate, cytosol, smooth microsomal, and Golgi fractions. The results suggest that hepatic uptake of propranolol is an extremely rapid process and essentially complete, independently of the dose. Effectively at 0.5 min, 70% and 85% of the low and high doses, respectively, were recovered in the liver homogenate. Furthermore following the 0.002-mg/kg dose, 96% of the recovered drug equivalents in the suprahepatic blood consisted of metabolites. An additional experiment demonstrated that the uptake of a 0.002-mg/kg dose of propranolol was not modified by a loading dose of 25 mg/kg. The pattern of propranolol distribution correlated with the intracellular localization of phospholipids and proteins. The amount of propranolol found in subcellular fractions relative to liver homogenate remained constant throughout the study, suggesting a rapid equilibrium. Low doses of propranolol were cleared from the hepatic cells almost completely by biotransformation. However, high doses saturated the metabolic clearance. Propranolol metabolites accumulated preferentially in the cytosol fraction. The intracellular elimination of the metabolites appeared to be a saturable process. The Golgi apparatus does not seem to be involved in the elimination of propranolol or its polar metabolites.     

Effect of diltiazem on the pharmacokinetics of propranolol,metoprolol and atenolol

Summary The pharmacokinetic interaction between diltiazem and three -adrenoceptor blockers propranolol, metoprolol and atenolol was investigated in healthy volunteers given diltiazem 30 mg or placebo t.d.s. for 3 days, followed by a single dose of propranolol 20 mg, metoprolol 40 mg or atenolol 50 mg.The AUCs of propranolol and metoprolol were significantly increased after diltiazem and it significantly prolonged the elimination half-life of metoprolol. In contrast, it did not significantly affect the pharmacokinetics of atenolol. Propranolol significantly decreased the resting pulse rate after diltiazem pretreatment as compared to placebo.The results indicate that diltiazem impaired the clearance of propranolol and metoprolol, which are principally metabolized by an oxidative pathway, and that the kinetic interaction between diltiazem and propranolol may partly be related to the significant reduction in the pulse rate produced by the latter.     

Pharmacokinetics and metabolism of oral doses of a 4′-methylthio derivative of propranolol in man

1. The objective of this study was to determine the oral dose pharmacokinetics and metabolism of 4′-methylthiopropranolol (MTP) in man and compare the results with observations for propranolol in previous studies.

2. Three women and five men received single oral doses of MTP, dose range 5-320 mg. Plasma concentration of MTP over time were measured by gas chromatography-mass spectrometry. MTP metabolites in urine were identified by comparative high-performance liquid chromatographic (HPLC) retention times and mass spectrometry with previously characterized reference compounds and quantified by HPLC.

3. The oral clearance of MTP of 1.2–1.41/min for the 80, 160 and 320 mg doses was about one third of the value previously reported for propranolol. The half-life for MTP (3.3–4.1 h) was, however, similar to that of propranolol. In contrast to propranolol, the peak (2.5 h) plasma concentrations of MTP increased linearly with dose (5-320 mg).

4. The oral clearance for MTP was about 2-fold higher in the men than in the women (P<0.01). In addition, the clearance of the (S)-enantiomer was about 30% higher than that of the (R)-enantiomer (P<0.05), which was a reversal of that seen with propranolol.

5. The metabolism of MTP resulted mainly in sulphur oxidation to sulphoxide and sulphone metabolites. These two metabolites accounted for 75% of the MTP dose. This switching from aromatic carbon oxidation for propranolol to sulphur oxidation for MTP is proposed as the basis of the lower oral clearance of MTP.

6. This study also demonstrated higher plasma binding of MTP (unbound fraction 3.7%) than of propranolol (10.5%; P<0.01), a factor probably contributing to decreased tissue distribution of MTP.     

PHARMACOKINETICS OF ACEBUTOLOL ENANTIOMERS AFTER INTRAVENOUS ADMINISTRATION OF RACEMATE IN A RAT MODEL: A DOSING RANGE COMPARISON

Acebutolol (AC) is a chiral β-adrenergic blocking drug, possessing intrinsic sympathomimetic activity (ISA), and is useful clinically as the racemate in treating hypertension. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of AC and its major metabolite diacetolol (DC) are reported after intravenous administration of single 5, 15, 30, and 50 mg kg⁻¹ doses of racemate to male Sprague–Dawley rats. The mean area under the plasma concentration versus time curve (AUC) values display a linear relationship with respect to the administered dose. No statistical differences are observed in apparent volume of distribution (V_d), terminal elimination half-life (t_1/2), total body clearance (Cl_t), or renal clearance (Cl_r) with respect to dose administered. Generally, R–S ratios for AUC following AC administration are statistically different from unity (p < 0·05). However, for the 50 mg kg⁻¹ doses the R–S ratio for AUC is not statistically different from one. For DC, the plasma disposition is nonstereoselective in plasma. The amount of R-DC recovered in urine, however, was greater than that of the antipode (R:S = 1·92 ± 0·29). This study suggests that the enantiomeric disposition of intravenous AC is linear within the investigated range of 5–50 mg kg⁻¹ racemate in rats. © 1997 John Wiley & Sons, Ltd.     

The effects of a beta-2 selective adrenergic agonist and a beta-nonselective antagonist on theophylline clearance

Beta-adrenergic agonists and antagonists have been shown to alter theophylline pharmacokinetics. It was the purpose of this study to characterize further the effects that terbutaline and propranolol have on theophylline disposition. In nine healthy male volunteers, mean parameters for theophylline disposition did not change after four days of terbutaline (5 mg q8h). Theophylline clearance, however, did change within the subjects. Clearance increased in five subjects, decreased in three, and remained unchanged in one volunteer. Pretreatment with four days of terbutaline (5 mg q8h) and propranolol (60 mg q8h) significantly decreased mean theophylline clearance (60.1 +/- 12.9 vs 40.6 +/- 9.9 mL/min/1.73m2; P less than .01) increased half-life (8.37 +/- 1.77 vs 12.32 +/- 2.70 hours; P less than .05), and increased postinfusion theophylline concentration (13.5 +/- 2.7 vs 18.95 +/- 2.5 micrograms/mL; P less than .001). In five subjects theophylline clearance increased after terbutaline pretreatment (64.6 +/- 13.0 vs 75.0 +/- 13.9 mL/min/1.73m2). The percentage increase ranged from 3.9 to 28.5%. These subjects were restudied after receiving propranolol alone (60 mg q8h). Comparison between the propranolol and terbutaline study and the propranolol alone study indicated no mean change in clearance in these five subjects (41.8 +/- 12.7 vs 36.1 +/- 5.1 mL/min/1.73m2). Thus it appears that the changes observed in these five subjects after terbutaline pretreatment may have been random in occurrence as has been shown to occur with theophylline disposition and are not related to terbutaline pretreatment. It is concluded that beta-2 adrenergic stimulation does not alter theophylline pharmacokinetics, whereas nonselective beta-adrenergic antagonism profoundly affected theophylline disposition. This is an additional reason not to use propranolol in patients who receive theophylline.