Effect of propranolol on free fatty acids of mice plasma during a passive avoidance test

Using the technique of Essman and Alpern (1964) on passive avoidance, the effects of propranolol (2 and 10 mg/kg i.p.) were studied on adult male Rockland mice. Avoidance is favored in the retest after 24 h by 2 mg/kg propranolol, but not by 10 mg/kg propranolol.Free fatty acids (FFA) in plasma significantly increase immediately after foot shock (FS) and the retest in control animals (saline); the 2 mg/kg dose of propranolol lowers the FFA level after FS and the retest, whereas 10 mg/kg of propranolol has no antilipolytic effect on FFA after FS. The effect of propranolol on retention would be independent of the FFA increase as observed at the end of the retest.A preliminary report of the present paper was presented at the Fifth International Congress on Pharmacology held in San Francisco, California, July 1972 (Abstract 389).Fellow of the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.     

Monitoring of the free concentration of cyclosporine in plasma in man

Summary The free fraction of cyclosporine A (CsA) and its total plasma concentration as determined by HPLC(CsA_T) were prospectively monitored in 66 recipients of renal transplants. The free CsA levels (CsA_u) were calculated.The variability in free CsA levels was no less than for total CsA_T levels. The correlation between CsA_u and CsA_T was high (r=0.90). Both CsA_T and CsA_u covaried with serum triglycerides and apolipoprotein A1.Fourty-four of the 66 patients suffered acute rejection episodes on 69 occasions. CsA_T and CSA_u both decreased and to a similar extent at the occurrence of acute rejection (42% and 59% decrease, respectively; significant vs baseline. Notsignificant difference in decrease in CsA_TvsCsA_u).Acute nephrotoxicity occurred on 11 occasions in 10 patients. Both CsA_T and CSA_u were approximately twice as high at the time of acute nephrotoxicity as compared to one week previously. Both CsA_T and CsA_u were higher during the first month after transplantation in patients with than in patients without systemic infection.Thus, plasma CsA_u gave no additional clinical information or guidance compared to CsA_T in renal transplant recipients. Due to the complexity of its assay, which requires two consecutive analyses, there does not appear to be any need for routine monitoring of CsA_u in renal transplant recipients.     

Fluorometric TLC determination of free and conjugated propranolol, naphthoxylactic acid, and p-hydroxypropranolol in human plasma and urine

Sensitive, specific, and reproducible TLC methods are described for the determination of propranolol and its major metabolites in humans, conjugated propranolol, free and conjugated naphthoxylactic acid, and free and conjugated p-hydroxypropranolol. The drug or metabolites are extracted from plasma or urine with ether and applied to TLC plates of silica gel or microcrystalline cellulose. After development, the plates are scanned in a spectrodensitometer equipped to measure fluorescence in the UV and blue regions of the light spectrum. Quantitation is achieved by comparing the areas under the peaks obtained from the unknowns to those obtained from standards applied to the same plate. Limits of quantitation in plasma are: free propranolol, 2 ng/ml; free p-hydroxypropranolol, 10 ng/ml; conjugated propranolol, 15 ng/ml; total (free and conjugated) naphthoxylactic acid, 25 ng/ml; and conjugated p-hydroxypropranolol, 50 ng/ml. These methods were used to obtain plasma level data in a volunteer after one single dose of propranolol and in patients under propranolol therapy. The Rf values of some known metabolites of propranolol obtained in various TLC developing systems are also presented.     

Quantitative TLC determination of propranolol in human plasma

A spectrodensitometric assay was developed for propranolol based on measurement of the absorbance of the drug on silica gel plates irradiated at 822 nm. Quantities as low as 0.10 microgram can be detected, and a linear relationship was obtained between 0.010 and 0.400 microgram. The percent recovery from plasma spiked with known amounts of the drug was 90.0--102.0. This procedure was used to determine propranolol in the plasma of patients receiving therapeutic doses of the drug.     

Increase in plasma propranolol caused by nicardipine is dependent on the delivery rate of propranolol

The influence of a single oral dose of nicardipine 30 mg on the pharmacokinetics and pharmacodynamics of propranolol 80 mg given as a conventional release formulation and as a slow release formulation was studied in two separate groups of 12 healthy volunteers. Nicardipine doubled the area under the curve (AUC) and C _max of propranolol when given as a conventional formulation, but increased it only slightly when given as a slow release formulation. This pharmacokinetic interaction did not result in clinically relevant changes in pharmacodynamic responses. These results indicate that the enhancement of the bioavailability of propranolol by coadministration of nicardipine is dependent on the delivery rate of propranolol, suggesting that the interaction is mainly due to short-term haemodynamic effects of nicardipine leading to saturation of hepatic enzymes or functional shunting.     

Cimetidine increases steady state plasma levels of propranolol.

1 The influence of cimetidine (1000 mg daily) on propranolol steady state plasma levels has been studied in seven normal volunteers. Cimetidine was used as a 200 mg normal release tablet whereas propranolol was given as a 160 mg slow release formulation once daily. 2 After 1 day of cimetidine treatment (day 9 of the study) the mean (Css) and minimal (Css min) propranolol steady state plasma levels increased significantly from 24.1 +/- 14.9 ng/ml (mean +/- s.d.) to 39.2 +/- 27.7 ng/ml (P = 0.01) and from 14.8 +/- 9.3 ng/ml to 27.1 +/- 21.2 ng/ml (P = 0.03), respectively. The apparent oral clearance (Clo) was reduced from 6.7 +/- 4.3 l/min to 4.6 +/- 3.11/min (P = 0.006). 3 A prolongation of cimetidine administration to 5 days (day 13 of the study) intensified this effect significantly (P = 0.02): Css of propranolol was elevated from 23.2 +/- 14.4 ng/ml to 44.9 +/- 26.7 ng/ml (P = 0.003); Css min was increased from 14.1 +/- 10.2 ng/ml to 28.4 +/- 17.9 ng/ml (P = 0.02) while Clo decreased from 6.9 +/- 4.1 1/min to 3.3 +/- 1.61/min (P = 0.006). 4 We conclude that the drug interaction between propranolol and cimetidine leads to significant elevations of propranolol steady state plasma concentrations which may cause a clinically relevant enhancement of the effect of a given dosage. This requires careful observation of patients under concomitant treatment with propranolol and cimetidine.     

Exercise-induced increments in plasma levels of propranolol and noradrenaline

Exercise-induced changes in the plasma levels of propranolol and noradrenaline were determined in nine volunteers. Total plasma propranolol levels were increased during submaximal treadmill exercise, with exercise-induced increments of 13 +/- 4% at 4 h after the last dose, 18 +/- 7% at 9 h and 41 +/- 5% at 16 h. Exercise-induced increments in plasma propranolol were observed after single as well as repeated doses. During exercise, increments in plasma propranolol were correlated temporally with changes in plasma noradrenaline. Exercise-induced increments in plasma noradrenaline were greater during propranolol administration than during placebo periods. The changes in plasma propranolol concentration during exercise may reflect a redistribution of propranolol at its site(s) of action.     

Sensitive high-pressure liquid chromatographic determination of propranolol in plasma.

A high-pressure liquid chromatographic method is presented for the determination of propranolol in human plasma. A reversed-phase cyanopropylsilane column was utilized with a liquid phase consisting of 70% acetonitrile and 30% 0.02 M acetate buffer, pH 7.0. A spectrofluorometric detector with an excitation wavelength of 276 nm and an emission filter with a 340-nm cutoff provided a detectable peak for 0.8 ng of propranolol/injection with this system. The reproducibility and precision of the method are shown from the analyses of samples containing 10--150 ng/ml of plasma.     

Effects of cholestyramine and colestipol on the plasma concentrations of propranolol

The effect of equivalent hypolipidaemic doses of cholestyramine (8 g) or colestipol (10 g) on the plasma concentrations of propranolol and 4'-hydroxypropranolol was studied in 12 normal volunteers following the oral administration of 120 mg of normal release propranolol tablets. When two doses of either cholestyramine or colestipol were administered prior to the propranolol, the peak plasma concentrations and area under the curve for both propranolol and the metabolite 4'-hydroxypropranolol were reduced significantly (P less than 0.05). We conclude that the drug interaction between cholestyramine or colestipol and propranolol leads to significant reductions in plasma concentrations of propranolol and 4'-hydroxypropranolol which may cause a clinically diminished effect for a given dosage. Therefore, patients should be observed when either of these resins are added to or deleted from a therapeutic regimen.     

Effects and plasma levels of propranolol and metoprolol in hyperthyroid patients

Summary The effects and plasma concentrations of different doses of propranolol and metoprolol were studied in 34 hyperthyroid patients. The initial daily doses were propranolol 160 mg or metoprolol 200 mg. If the resting heart rate remained above 75 beats per min after treatment for 4–7 days, the dose was increased and the patient re-examined after a further 4–7 days. Propranolol (n=17) caused a reduced heart rate, a decrease in serum 3,3,5-triiodothyronine (T3) and an increase in serum 3,3,5-triiodothyronine (reverse T3, rT3). In 10 patients, there was no change in T3 or rT3 until the daily dose of propranolol had been increased to 240 or 320 mg. The plasma level of propranolol was significantly correlated with the decrease in T3 and the increase in rT3. Metoprolol (n=17) caused a reduction in heart rate similar to that following propranolol. However, serum T3 was only slightly reduced even after an increase in dose to 300 or 400 mg, and serum rT3 was not altered. Metoprolol concentrations were not significantly correlated with the fall in T3. It appears that the influence of-blockers on T4 conversion is of little importance for the clinical improvement in hyperthyroid patients, and rather it is a consequence of ₁-adrenergic blockade interfering with the effect of T3. In addition, the findings support the assumption that therapeutic failure with-blockers in hyperthyroidism may be due to suboptimal treatment, and that individualized dosage is necessary.     

Monitoring free drug concentrations: challenges

Measurement of drug concentrations in biological samples is of utmost importance in many research areas. The information about the amount of drug in a biological sample can be given as either total concentration, which ignores the interaction of the drug with the sample matrix, or as free concentration, which shows the portion of molecules able to diffuse through membranes and exert biological activity. Although the historical trend has been towards determining total concentrations, measurement of free concentrations is becoming more important since it correlates better with pharmacological and toxicological effects. This review will discuss the most popular experimental approaches for monitoring free drug concentrations, based on the type of sample to be investigated and the kind of information to be collected. It is shown that the current challenges in measuring free concentrations are: convenience, accuracy, precision, wide applicability, availability of accurate and precise reference methods, ruggedness, and standardized sample conditions.     

Time course of plasma levels and electrophysiologic effects of propranolol in man

We studied the time course of three electrophysiologic effects of propranolol after intravenous and oral administration and their relationship with plasma levels within the same subjects. Ten patients who had undergone cardiac catheterization for diagnostic purposes received 0.1 mg/kg of propranolol intravenously. Blood was drawn at intervals for 12 hr and heart rate and the effective refractory periods of the atrium (ERPA) and the atrioventricular node (ERPAVN) were determined at the same time. Eight patients continued treatment with propranolol by the oral route for up to 4 days (40 mg every 12 hr). Blood was sampled after each morning dose. Plasma concentrations of propranolol were measured by gas chromatography. Maximal lengthening of ERPA after propranolol (15.1% i.v. and 9.4% oral) was much less marked than that of ERPAVN (23.2% i.v. and 19.4% oral). Heart rate decreased 23.5% (i.v.) and 13.1% (oral). Effects were seen much sooner after intravenous (5-8 min) than after oral administration (86-146 min), but they lasted about twice as long after oral as after intravenous treatment.