Biomedical subjects
Publications and source records attributed to A Yacobi.
The extent of biliary excretion of hydroxyethyl starch (HES) in man after intravenous administration of 500 ml of a 6% solution to nine healthy male volunteers was determined using a specific gas chromatograph mass spectrometer selected ion monitoring procedure. On the average, less than 1% of the administered dose was recovered in feces over a 14 day period.
Esmolol is an ultra-short-acting beta-blocker currently in Phase II clinical trials. The ester functionality in esmolol results in rapid metabolism of the beta-blocker into an acidic metabolite and methanol. Dichloromethane was used to denature blood esterases and quantitatively extract esmolol from the blood. A deuterated analogue of esmolol was selected as the internal standard, and both compounds were chromatographed as the trimethylsilyl derivatives. Blood levels of esmolol were quantitated by gas chromatography-mass spectrometry with selective-ion monitoring, focusing on specific ions corresponding to esmolol and the internal standard. The lower limit of sensitivity of the assay was 2.5 ng/mL. Using the assay, blood samples from a dose-ranging study in humans were analyzed for concentrations of esmolol. Steady-state blood levels of esmolol after intravenous infusion rates of 40, 100, 200, 300, 450, and 650 micrograms/kg/min were 0.202, 0.464, 0.977, 1.31, 1.92, and 2.97 micrograms/mL of blood. The elimination t1/2 and total body clearance were estimated to be approximately 10 min and 220 mL/kg/min, respectively. The high clearance of esmolol suggested that metabolism by blood esterase(s) was the primary determinant of the duration of action of the drug.
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This investigation was designed to determine if the reported stereoselectivity of the pharmacokinetic interaction between warfarin and metronidazole in humans occurs also in rats and if the potentiation of the anticoagulant effect of warfarin can be ascribed solely to inhibition of warfarin metabolism by metronidazole. Metronidazole had no effect on the serum protein binding of racemic warfarin in vitro over a wide concentration range but decreased the protein binding of R-(+)-warfarin and S-(-)-warfarin in vivo, perhaps indirectly through metabolite(s). Treatment with i.p. metronidazole, 100 mg/kg every 6 hr, decreased the plasma clearance of free warfarin ("intrinsic clearance"). This inhibitory effect was more pronounced with S-(-)-warfarin than with R-(+)-warfarin (congruent to 60 and congruent to 30%, respectively). Metronidazole did not affect plasma prothrombin complex activity in vitro but reduced it in vivo. Metronidazole treatment increased the elimination rate constant for endogenous prothrombin complex activity and decreased the plasma concentration of free R-(+)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal (there were insufficient data to determine the effect of metronidazole on the activity of the other enantiomer). It is concluded that metronidazole preferentially inhibits the metabolism of S-(-)-warfarin in rats as in humans but that (at least in rats) the stereoselectivity is not absolute. Moreover, metronidazole has an indirect inhibitory effect on warfarin protein binding in vivo and also affects the pharmacodynamics of warfarin as well as the blood clotting process per se.
The purpose of this investigation was to explore the mechanisms and possible stereoselectivity of the interaction between warfarin and chloramphenicol in rats. Chloramphenicol had no apparent effect on the serum protein binding of R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo. Treatment with i.p. chloramphenicol, 50 mg/kg every 4 hr or 30 mg/kg every 6 hr, decreased the plasma clearance of free warfarin by one-half or more, with no apparent stereoselectivity. The volume of distribution was not significantly affected; the half-life of each warfarin enantiomer was appreciably increased by chloramphenicol. Treatment with chloramphenicol had no apparent effect on relative liver size and on serum aspartate aminotransferase activity. Prothrombin complex activity in plasma was not affected by in vitro addition or in vivo administration of chloramphenicol alone. Chloramphenicol treatment did not affect significantly the elimination kinetics of endogenous prothrombin complex activity and the plasma concentration of free R-(+)-warfarin or S-(-)-warfarin required to decrease prothrombin complex activity synthesis rate to one-half of normal. It appears that the pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due only to inhibition of warfarin metabolism and that this effect is not stereoselective.
Hydroxyethyl starch (HES) found in rat serum and spleen after single and daily administrations of 0.9 g/kg for 1 week was characterized by gas-liquid chromatography. There was very little difference in the degree of substitution (D.S.) and molar substitution (M.S.) of HES in serum samples obtained at 1 hour and 57 days after multiple doses and of HES in spleen samples obtained at 1 hour and 168 days after a single dose of HES. The small increase in D.S. and M.S. was due to a decrease in the glucose content and not due to a change in the ratio of mono- to poly-substituted glucoses.
The distribution of [14C]bretylium tosylate in the body and the relationship between tissue and plasma concentrations was determined following intravenous administration of the drug to Charles River rats. The renal excretion of bretylium was rapid in rats and follows an active process. On the average, 50% of the administered dose was excreted in the urine within 1 hr. In the postequilibrium phase, the plasma concentration declined with a half-life of 5 hr. Bretylium concentrations in all tissues, except the heart, declined rapidly according to a triexponential equation. The liver and kidney bretylium concentrations declined in parallel to the plasma concentration with mean tissue-plasma concentration ratios of 6.04 and 12.3, respectively, in the beta phase. However, the concentration of bretylium in the heart increased gradually and peaked at 2 hr, with a tissue-plasma concentration ratio of 121, which, in turn, declined to a value of greater than 60 after 8 hr. The data indicated that (a) bretylium is rapidly distributed into the liver and kidney immediately after reaching the systemic circulation; (b) the distribution into the heart occurs at a slower rate compared with the other organs, and the drug has a high affinity to the myocardium; and (c) since the heart is the site of action and there is no direct correlation between the concentrations in myocardium and plasma, the antiarrhythmic effect of bretylium may not be related to the plasma concentration.
beta-Adrenergic blocking agents--esmolol hydrochloride, pharmacokinetic profile, metabolism. Pharmacokinetic profile--cardioselective beta-adrenergic blocking agent, methyl 3-[4-(2-hydroxy-3-(isopropylamino)propoxy]phenylpropionate hydrochloride. Esmolol--cardioselective beta-adrenergic blocking agent, pharmacokinetic profile.
The pharmacokinetics of N-acetylprocainamide, administered orally or intravenously, were studied in 3-, 6-, and 12-month-old rats using a two-way crossover study design. At 3, 6, and 12 months of age, the half-life values of N-acetylprocainamide were 1.66, 1.82, and 2.29 hr, respectively; the apparent volumes of distribution were 4.75, 3.35, and 1.98 liter/kg, respectively. The elimination rate constant, clearance, and absolute bioavailability of the drug (determined by AUC measurements and the amounts excreted unchanged in the urine) decreased significantly with age. The rate of absorption remained unchanged. The amounts of N-acetylprocainamide in the liver and kidneys were significantly higher in the 12-month-old animals. These results clearly demonstrate a significant alteration with age in the bioavailability, distribution, and elimination of N-acetylprocainamide in rats. In long-term toxicity studies of this and other drugs that show age-dependent pharmacokinetics, an adjustment in the chronically administered dose is essential.
Esmolol is an ultra-short-acting beta blocker. Its kinetics was studied in eight healthy subjects after continuous intravenous infusion of 400 micrograms/kg/min over 2 hr. The concentrations of esmolol and its major metabolite, 3-[4-(2-hydroxy-3-[isopropylamino]propoxy)phenyl]propionic acid, in blood and urine were determined by gas chromatographic-mass spectrometric assay and HPLC. The distribution and elimination t1/2s of esmolol averaged 2.03 and 9.19 min. The apparent volume of distribution of esmolol averaged 3.43 l/kg and was four times the volume of the central compartment. The total clearance of esmolol averaged 285 ml/min/kg, indicating that nonhepatic routes play a predominant role in its clearance. The t1/2s of formation and elimination of the metabolite averaged 2.82 min and 3.72 hr. The ratio of the metabolite formation and elimination rate constants of the parent drug (kf/k10) averaged 0.829, suggesting that 82.9% of esmolol was converted to the metabolite (which is consistent with the urinary recovery of 71% of the dose as unconjugated metabolite). The volume of distribution and total clearance of the metabolite averaged 0.411 l/kg and 1.28 ml/min/kg. Esmolol was followed by a significant reduction of isoproterenol-induced increase in heart rate and systolic blood pressure at doses of 50, 150, and 400 micrograms/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)
Bretylium kinetics were examined in patients with varying degrees of renal impairment after a single intravenous dose of bretylium tosylate. Maximum plasma concentrations achieved at the end of the infusion, when normalized to the dose, correlated strongly with creatinine clearance. Drug disposition from plasma was biexponential, with a short distributive phase, but drug elimination was reduced, especially in patients with creatinine clearance below 30 ml/min X 1.73 m2. There was reduction in renal and total clearance and prolongation of t 1/2, with deteriorating renal function. In one patient who was reevaluated after a year, there was 76% reduction in the total clearance, corresponding to 43% deterioration of renal function. The difference of 33% between these values is due to a reduction of nearly 36% in volume of distribution, caused by the further deterioration of the renal function. Six-hour hemodialysis procedure on two anephric patients, resulted in an apparent one- to threefold increase in the computed bretylium clearance during dialysis, but the fraction of the total body load eliminated during the same period was not proportionally significant. The strong linear relationships between renal and total clearance, beta, and the creatinine clearance, may be helpful in adjusting dosage regimens for bretylium in patients with renal dysfunction.
During the past few years, there have been rapid changes in the pharmaceutical uses of nitroglycerin. New dosage forms and new delivery systems have become available, which have resulted in potential confusion to all concerned with the proper use of these systems. The goal of this review is to prevent confusion and to bring all the relevant information together. The various analytical techniques available for quality control of the dosage forms and for the study of the pharmacokinetics are reviewed, with the intent of enabling the reader to identify pertinent references rapidly. The interaction of nitroglycerin with packaging and plastic delivery devices is also reviewed so that the reader can make informed choices. Finally, the clinical pharmacy and pharmacokinetics are reviewed so as to bring the reader up to date in that area. After reading this article, the areas of nitroglycerin research that still need to be explored should be apparent.
Hetastarch, ethoxylated amylopectin, has found clinical utility as a plasma volume expansion agent, a sedimenting agent during pheresis, and a pump priming fluid. Hetastarch is a complex mixture of derivatized amylopectin molecules of various molecular sizes. The derivatization causes resistance to enzymatic hydrolysis, therefore, allowing hetastarch sufficient vascular residence time to be an effective vascular osmotic agent. This has led to its use as a volume expander and to its consequent use as a pump priming fluid. The metabolism of hetastarch proceeds through alpha-amylase hydrolysis of glycosidic bonds, yielding molecules small enough for renal clearance, but does not result in complete hydrolysis. Hence, glucose is not a significant product of hetastarch metabolism. Metabolism proceeds at such a rate that volume expansion is seen for 24-36 hours with a maximum effect (100-172 percent of the infused volume) occurring shortly after infusion. Ninety percent of the dose is eliminated with a half-life of about 17 days.
To determine the elimination of high-molecular-weight hydroxyethyl starch (HES, Mw 450,000) in normal subjects, ten volunteers were given 500 ml 6% HES solution by intravenous infusion, and serial blood and urine samples were collected for nonglucose total carbohydrate determination. On the average, 46 and 64 per cent of the dose was excreted in the urine within two and eight days, respectively. The plasma concentration declined rapidly during the first week after infusion. The average terminal half-life was 17 days during the first 42 days, which accounted for elimination of about 90 per cent of the dose. The remainder was eliminated with a terminal half-life of 48 days determined between days 42 and 83 of the study. As expected, the infusion of HES resulted in plasma volume expansion over a 48-hour period during which time levels of nonglucose carbohydrates were above 3.5 mg/ml. HES is metabolized by alpha-amylase in the body. During the first 48 hours after infusion of HES, plasma alpha-amylase activity was significantly increased over control. Concomitantly, alpha-amylase activity in urine was also elevated but not significantly so.
The pharmacokinetics of bretylium in dogs and the efficacy of hemoperfusion with a resin column in its removal from the body following intravenous administration of bretylium tosylate were investigated. Five mongrel dogs weighing 18-26 kg were given a bolus dose of 15 mg/kg. Serial blood samples were taken for 24 hr. Hemoperfusion, through a resin column, was then initiated and continued for 4 hr under pentobarbital anesthesia. During hemoperfusion, arterial and venous blood samples were collected several times; venous blood samples were then withdrawn for an additional 8 hr. Urine was collected from each dog in three portions for up to 48-54 hr. Pharmacokinetics of bretylium in dogs could be characterized by a two-compartment open model with a distribution half-life of 7 min and biological half-life of 15.9 +/- 1.9 hr. Plasma levels declined rapidly from approximately 20 microgram/ml at 6 min to less than 2 microgram/ml within 1 hr. The ratio of intercompartmental rate constants, k12/k21, was 16.7, and the volume of the central compartment and apparent volume of distribution were 0.245 and 5.22 liter/kg, respectively, indicating a wide distribution of bretylium into the tissues. Plasma dialysis clearance averaged 29.7 ml/min, which is 30% of the total body clearance (98.8 ml/ min). These data suggest that resin hemoperfusion may not be useful in the treatment of bretylium intoxication.
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The elimination of high molecular weight hydroxyethyl starch (HMW-HES) was determined in dogs. . Eight dogs were divided into two groups; one of which was bled 25 ml/kg. Both groups were given 25 ml/kg of 6% HMW-HES solution over a 30 min period. There was no significant difference in plasma concentration vs time profiles between the two groups. The biological half-life estimated between days 7-28, averaged 7.5 and 8.4 days in control and bled dogs, respectively. The renal clearance of HMW-HES diminished considerably in both groups during the 7 day period. Despite large interanimal variations in renal clearance, there was not a significant difference between groups.