Prediction of In Vivo Atenolol Removal by High-Permeability Hemodialysis Based on an In Vitro Model

Purpose. In order to update our data on drug dialyzability using the high-permeability dialysis membranes, atenolol elimination by an in vitro dialysis model was compared to that observed in six patients during high-permeability hemodialysis (HD), and the predictive value of the model was evaluated. Methods. Atenolol clearance was evaluated in six patients undergoing chronic HD. They were considered as eligible candidates if they were between 18 and 80 years of age, had a body mass index between 19 and 30 kg/m2, underwent HD and were taking atenolol on a regular basis in oral tablet form for at least 1 month before the study started. Atenolol clearance was also evaluated in three in vitro dialysis sessions with high-permeability polysulfone membrane. Atenolol was dissolved in 6 L of Krebs-Henseleit buffer with bovine serum albumin. Dialysis parameters were set to mirror as much as possible the patients’ parameters (flow rate: 300 mL/min, dialyzate flow: 500 mL/min). After sample collection, drug concentrations were measured with high performance liquid chromatography. The comparison between in vivo and in vitro atenolol elimination kinetics was performed by drawing the curve fittings of concentrations vs. time on SigmaPlot 12, and adding a 95% prediction interval to each elimination curve fitting. Results. Mean dialysis clearance of atenolol in vitro and in vivo was 198 ± 4 and 235 ± 53 mL/min, respectively. Atenolol was significantly removed within the study time period in both in vitro and in vivo experiments. By the end of in vitro dialysis, atenolol remaining in the drug reservoir was less than 2% of initial arterial concentration. Conclusion. Our study has indicated that atenolol is almost entirely cleared during high-permeability hemodialysis. Furthermore, the in vitro prediction interval of the drug elimination curve fitting could forecast its in vivo elimination especially at the end of dialysis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Pharmacokinetic Evaluation of a Case of Massive Sotalol Intoxication

OBJECTIVE: To describe serum concentrations and clearance of sotalol after a massive overdose. CASE SUMMARY: A 37-year-old white man took 11.2 g of sotalol hydrochloride tablets in a suicide attempt. The first serum d,l-sotalol concentration 3 hours after taking the first tablet was 20.6 mg/L and the last measured concentration 59 hours later was 1.8 mg/L. Logarithmic transformation of the concentration data indicated two separate monoexponential phases in the elimination curve, with half-lives of 30.1 and 11.6 hours. DISCUSSION: The shorter serum half-life in the later phase is comparable with that in four previously reported sotalol intoxications and within the normal range. The elimination rate increased in a temporal manner with an increase in systolic blood pressure about 30 hours after the patient was admitted. Since the sotalol elimination rate depends principally on renal function, we believe the initially slow elimination is due to a temporary reduction of the renal function caused by the systolic hypotension. CONCLUSIONS: An initial phase of slow sotalol elimination may occur after severe overdoses. In our patient this was probably due to hypotension. Thus, blood pressure should be monitored carefully.

Elimination rate of 65Zn as a measure of food intake: a validation study in the mouse (Mus sp.)

We measured elimination of 65Zn in white mice (Mus musculus) using daily whole body counting. Thirteen male mice were randomly divided into three groups, each maintained at a different temperature. Each animal was labeled with 65Zn on day 0 and monitored over days 0–48 postinjection. Daily food intake and body masses of all the animals were measured. We evaluated the ability of derived components of the 65Zn elimination curves to predict food intake over different phases of the measurement period. Food intake was significantly different between temperature groups; temporal variation in food intake was not intercorrelated between groups. Whole body elimination of 65Zn involved a rapid decline over days 0–1, followed by a biexponential decline in counts over days 1–48. Components of the first phase of the biexponential elimination curve were not significantly related to food intake. The rate (k2) of isotope elimination in the second phase was significantly related to mean food intake over days 25–48, 13–24, and 37–48. Rate of turnover in the second phase of elimination, incorporating the variation in zinc body pool size (k2 x 1/N2), where N2 is the constant of the second phase of elimination, was the best predictor of food intake and accounted for 60% of the variability over days 37–48.

Detection of heterozygotes for phenylketonuria. Total body phenylalanine clearance and concentrations of phenylalanine and tyrosine in the plasms of fasting subjects compared.

Two tests have been compared for detection of heterozygotes for phenylketonuria, one based on determination of plasma phenylalanine and tyrosine concentrations in fasting individuals and the other on kinetic evaluation of the plasma elimination curve after intravenous loading with L-phenylalanine. The plasma elimination curve was biexponential and the kinetics were evaluated according to the two-compartment model. The constant, beta, expressing the rate of elimination from plasma at pseudo-equilibrium, the rate constant for the elimination from the central compartment, and the total body clearance were determined. Of these three, total body clearance, which on the average was reduced by 32% in the phenylketonuric heterozygotes, showed the best discriminatory ability, but was not better than the information on concentrations of phenylalanine and tyrosine in detecting heterozygotes for phenylketonuria.

Turnover Studies of Des-A Fibrin and Fibrinogen in Healthy Human Beings

Soluble fibrin was injected into man. Two methods were used to prepare soluble des-A fibrin. Purified human 1-125-fibrinogen was transformed into soluble des-A fibrin (des-A FM):(1) by thrombin in the presence of 2.0 M urea (method according to Hogg and Blombäck, 1975), (2) by ancrod. Eight male volunteers were injected either with thrombin-induced soluble I-125-fibrin (FM-T) or ancrod-induced soluble I-125-fibrin (FM-A). The control consisted of I-131-fibrinogen injected simultaneously with soluble I-125-fibrin.The mean distribution volume of des-A FM-T was 48.9 ml/kg and that of des-A FM-A 50.3 ml/kg which is similar to that of the injected fibrinogen (43.0 ml/kg) indicating a homogenous distribution of the injected FM in the circulating blood. The injected des-A FM disappeared faster from the circulating blood than des-AB fibrin monomer. Six hours after injection 99.5% of the injected FM-A and 95% of the injected FM-T were removed from the circulating blood. The FM were cata-bolized since free I-125 were quantitatively recovered from the urine. The elimination curve of des-A FM-A as well as des-A FM-T does not represent a mono-phasic exponential decay.The experiments demonstrate that des-A fibrin can be traced in man and is cleared from the circulating blood at a high elimination rate.(Supported by the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg)

Behaviour of Soluble DES-AB Fibrin and Fibrinogen in Man

Human des-AB fibrin was generated from I-131-fibrinogen by clotting with thrombin in the presence of EDTA and aprotinin, and solubilized in buffered urea. About 1 to 2 mg of fibrin was injected simultaneously with I-125-fibrinogen dissolved in buffered urea into 14 male healthy volunteers.The mean distribution volume of the soluble fibrin was 48.5 ml/kg in comparison to 46.1 ml/kg of the injected fibrinogen demonstrating a homogeneous distribution of both the labelled proteins in the circulating blood. The elimination characteristics of the soluble fibrin did not represent a monophasic exponential decay. 24 hours after injection a mean of 24.3 % of the initial value of the fibrin was traced in the blood in comparison to a mean of 53.3 % of the fibrinogen at that time. The terminal slope of the fibrin elimination curve between 2 and 8 days after injection was a monophasic exponential curve with a mean T 1/2 of 2.3 days. The fibrinogen elimination curve showed a T 1/2 of 4.2 days during that period of time.These experiments indicate that solubilized fibrin injected into man can be traced in the circulating blood for a long period of time. The catabolic behaviour of fibrin differs significantly from that of fibrinogen.

“Alveolar plateau” of the single breath nitrogen elimination curve in normal subjects

The single breath N2 elimination test, as standardized by Comroe and Fowler, has been used in normal subjects. The N2 difference, i.e. the difference in N2 concentration between Ve = 1250 and Ve = 750 ml, showed a tendency to increase with increasing volumes of inspired O2 and with increasing inspiratory flow rates. It decreased with increasing breath-holding time and was not consistently influenced by expiratory flow rate. The findings are compared with those of Fowler and of Shephard on normal subjects; different results were obtained, largely depending on different analytical procedures. These factors must be considered when evaluating results in patients. Submitted on July 21, 1958