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Biomedical subjects

D D Shen

Publications and source records attributed to D D Shen.

At least 91 records · Page 5Linked to original sources
PubMed1984

Effect of renal failure and bis(2-ethylhexyl) phthalate pretreatment on the disposition and metabolism of antipyrine in the rat.

Renal failure patients undergoing hemodialysis are regularly exposed to phthalate plasticizers leached from dialysis tubings. Previous studies have shown that antipyrine is eliminated more rapidly in chronic renal failure patients compared with normal individuals. Therefore, the effect of bis(2-ethylhexyl) phthalate on the metabolism of antipyrine was investigated in normal and renal failure rats. In normal animals, the elimination kinetics of an intravenous dose of antipyrine (20 mg/kg) was determined before and after 14 days of peroral treatment with 2 mL/kg/d of bis(2-ethylhexyl) phthalate. The plasma clearance of antipyrine increased markedly after bis(2-ethylhexyl) phthalate treatment. There was a corresponding decrease in the elimination half-life of antipyrine, whereas the apparent volume of distribution was not affected. Both liver weight and hepatic cytochrome P450 content increased following exposure to bis(2-ethylhexyl) phthalate, indicating the induction of hepatic microsomal enzymes. The fractional urinary recovery of the N-demethyl, 4-hydroxy, and 3-hydroxymethyl metabolites of antipyrine was not altered, suggesting that all three oxidative pathways were induced to the same extent. Renal failure alone did not affect the elimination kinetics of antipyrine. However, antipyrine clearance was induced to a greater extent by bis(2-ethylhexyl) phthalate treatment in the renal failure rats as compared with the control animals. The potential for phthalate plasticizers to alter hepatic drug metabolism in hemodialysis patients should be considered.

Animals↗
PubMed1984

Pharmacokinetics of l-propranolol during repetitive dosing in normal and uranyl nitrate-induced renal failure rats.

The effect of experimental renal failure on the intravenous and oral pharmacokinetics of l-propranolol was studied in rats. Renal failure was induced by a single intravenous injection of uranyl nitrate (5 mg/kg). Pharmacokinetic studies were carried out on the fifth day after injection of the renal toxin (renal failure group) or saline (control group). Serum concentration time course of l-propranolol was characterized after a single intravenous or oral dose as well as after five consecutive doses of the drug given at 3-hr intervals. During repetitive intravenous drug administration, steady state was reached by the second dose, i.e., within 6 hr after initiation of repetitive dosing. No significant difference in the serum concentration time course of l-propranolol was observed between control and renal failure animals. In both groups the AUC over the steady-state dosing interval was on the average 21-27% higher than the AUC after a single dose, indicating a slight decrease in the systemic clearance of l-propranolol during repetitive intravenous drug administration. An approximately two- to three-fold higher serum l-propranolol concentration was observed in renal failure animals as compared to the normal controls after both single or repetitive oral dosing. The apparent reduction in oral clearance probably reflected an inhibition of the hepatic first-pass metabolism of l-propranolol in the renal failure rat. An unexpectedly high and protracted accumulation of serum l-propranolol concentration was observed during repetitive oral drug administration. Continuing accumulation was still evident after the fifth oral dose, i.e., a period of 15 hr or approximately 10 half-lives. The mean AUC over the last dosing interval was 32.0 and 17.8 times higher than the predicted steady-state estimate based on single oral dose data for control and renal failure rats, respectively. The substantial reduction in the oral clearance during repetitive drug administration may be due to an auto-inhibition of l-propranolol metabolism.

Acute Kidney Injury↗
PubMed1984

Use of pharmacokinetic profile in evaluating patients with repeatedly low theophylline concentrations.

Assessment of individual pharmacokinetics has been helpful in the evaluation of patients with persistently low serum theophylline concentrations and poorly controlled asthma. This paper presents seven cases where pharmacokinetic profiling specifically identified the etiology for low theophylline concentrations. Pharmacokinetic profiles were done following oral or intravenous dosing of theophylline. Serial blood samples drawn over 12 hours were assayed for theophylline concentrations using HPLC. Serum half-life (t1/2), clearance (Cl), volume of distribution (VD) and time-to-peak concentration were determined for each subject. In this series, three patients exhibited rapid theophylline clearance, two had predictable theophylline pharmacokinetics, and two presented with unique pharmacokinetics. These cases illustrate a wide range of pharmacokinetic behavior seen in clinical practice. To evaluate patients with persistently subtherapeutic theophylline concentrations, determination of individual pharmacokinetic profiles should be performed before prescribing high doses of theophylline (greater than 30 mg/kg/day).

Asthma↗
PubMed1984

Dose-dependent pharmacokinetics of antipyrine in the rat.

In rats given a single intravenous dose, the disposition of antipyrine was dose-dependent and followed apparent first-order kinetics only at the lowest (20 mg/kg) dose administered. The initial rate of disposition decreased with increasing dose, indicating apparent saturation of antipyrine metabolism. The observed nonlinearity was unusual in that the terminal elimination rate increased significantly with increasing dose, suggesting that autoinduction of metabolism may occur after a single exposure to antipyrine. The potential implications of dose-dependent antipyrine pharmacokinetics for the use of antipyrine as a model substrate in the estimation of hepatic microsomal oxidative enzyme activity are discussed.

Animals↗
PubMed1983

Effect of experimental renal failure on the disposition kinetics of l-propranolol in rats.

The effect of uranyl nitrate-induced renal failure on the pharmacokinetics of the levo-isomer of propranolol in rats was investigated. The serum clearance of an i.v. dose of propranolol (1.5 mg/kg) in normal animals approached hepatic blood flow, suggesting that the systemic clearance of the drug is rate-limited by blood flow to the liver. Extensive first-pass metabolism was observed after oral administration of l-propranolol was only 7%. Renal failure had no apparent effect on the distribution and elimination of i.v. administered l-propranolol. In contrast, the area under the serum drug concentration time curve after oral administration was increased from 6.95 to 19.3 micrograms X min/ml, which corresponded to a 2.5-fold increase in the systemic availability of l-propranolol (from 7 to 18%). The gastrointestinal absorption of l-propranolol, as assessed by comparing the urinary recovery of radioactivity after i.v. and oral administration of l-[3H]propranolol, was complete in normal animals. Hence, an increase in the extent of absorption of l-propranolol in renal failure cannot be offered as a cause of increased systemic availability. Neither the in vitro nor the in vivo serum protein binding of l-propranolol differed between renal failure and control animals. The intrinsic metabolic clearance of unbound l-propranolol in renal failure rats is estimated to be about 60% lower than that in control rats. These results suggest that the previously reported increase in propranolol serum concentration after oral administration of the drug to uremic patients is due to decreased presystemic biotransformation of the drug.

Acute Kidney Injury↗
PubMed1983

Alterations in serum protein binding and pharmacokinetics of l-propranolol in the rat elicited by the presence of an indwelling venous catheter.

Preliminary investigations in the rat revealed some unexpected alterations in the pharmacokinetics of l-propranolol when single dose studies were performed on two separate occasions 7 days apart. The apparent volume of distribution of l-propranolol was found to be consistently lower on the second study day. Also, the systemic availability of orally administered propranolol (6 mg/kg) increased from 4.1 to 7.8% from the 1st to the 2nd study day, indicating a decrease in the presystemic clearance of the drug. These changes were associated with a 50 to 60% decrease in the serum unbound fraction of l-propranolol between the 2 study days. Further investigations revealed that the time-dependent increase in the serum protein binding of l-propranolol was elicited by the presence of an indwelling venous catheter which was surgically implanted for the purpose of blood sampling. In contrast, a slight decrease in the serum protein binding of an acidic drug, phenytoin, was observed after catheter implantation. These changes in serum drug protein binding were readily reversed when the indwelling catheter was removed. The total serum protein concentration was not affected by catheter implantation. Fractionation of serum proteins by electrophoresis revealed an increase in alpha 1- and gamma-globulin fractions, a slight decrease in serum albumin and no change in beta- and alpha 2-globulin fractions. Competitive protein binding studies with tris(2-butoxyethyl)phosphate, a specific ligand to alpha 1-acid glycoprotein (AAG), indicate that the increase in serum l-propranolol binding was largely due to an elevation in serum AAG. These observations also explain the opposite effect of catheterization on the serum protein binding of phenytoin, which is bound largely to serum albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

An improved high-pressure liquid chromatographic assay for secobarbital in serum.

A high-pressure liquid chromatographic method for the analysis of secobarbital in serum was developed. Secobarbital was extracted from buffered serum (pH 5.5) with a solvent mix of hexane-ether-n-propanol. 5-(4-Methylphenyl)-5-phenylhydantoin was added as an internal standard. Separation of secobarbital and internal standard from serum constituents and other drugs was achieved on a 5-mum C-18 reversed-phase column using an acetonitrile-phosphate buffer (pH 4.4) mobile phase. The eluent was monitored at 195 nm. The sensitivity limit of the assay was approximately 0.02 microgram/ml with 0.5 ml of serum sample. The application of this method to pharmacokinetic studies in pediatric patients was demonstrated.

Child, Preschool↗
PubMed1982

Rectal absorption and disposition of secobarbital in epileptic children.

The absorption and disposition of rectally administered secobarbital was studied in ten epileptic children, ages 2-13 yrs. Five subjects received secobarbital rectally in solution, and the other five received secobarbital suppositories. Concentration of secobarbital in serum was serially determined during 48 hrs after a single rectal dose of about 5 mg/kg. The rate of absorption of secobarbital, as measured by the time to reach peak serum concentration, was much more rapid from the solution than the suppository (0.92 +/- 0.47 hr vs 4.60 +/ 2.30 hr). The peak serum concentration of secobarbital in the solution group was consistently higher than in the suppository group (2.26 +/- 0.37 micrograms/ml vs 1.35 +/- 0.24 microgram/ml). None of the individual peak serum concentrations exceeded 3 micrograms/ml, which is well below the previously reported minimum toxic concentration of secobarbital (ie, 6 microgram/ml). The elimination half-life of secobarbital varied over a wide range, from 2.7 to 13.5 hr, and is, on the average, shorter than estimates previously reported for adult volunteers or poly-drug abusers. Also, the mean elimination half-life did not differ between the solution and the suppository groups. The extent of rectal absorption of secobarbital, as assessed by the area under the serum concentration time curve, was not significantly different between the solution and the suppository treatments. If rectal secobarbital is considered for treatment of prolonged seizure, a rectal solution may offer a more rapid and consistent onset of action than with the suppository preparation.

Adolescent↗
PubMed1982

Rapid elimination of quinidine in pediatric patients.

The oral absorption and elimination of quinidine in pediatric patients was studied. Single oral doses of quinidine sulfate were administered to 13 patients ranging in age from 4 to 22 years of age. Serum quinidine concentration reached a peak within 30 minutes to two hours after drug administration. The serum half-life of quinidine varied from 2.5 to 6.7 hours and was, on the average, shorter than the reported estimates for adult volunteers and cardiac patients (means ranging from 4.9 to 7.3 hours). Hence more frequent dosing or the use of slow-release preparations may be necessary in some pediatric patients in order to avoid excessive fluctuation in serum drug concentrations over a dosage interval. The oral dose clearance of quinidine (ie, oral dose divided by the area under the serum concentration time curve) varied over a threefold range, from 0.151 to 0.570 liter/hr/kg, and was found to correlate inversely with age (r = .80). In comparison with mean clearance estimates that have been reported for normal adult volunteers (0.293 +/- 0.078 liter/hr/kg), children less than 12 years of age (0.461 +/- 0.117 liter/hr/kg) were found to have significantly higher clearances, whereas no difference was observed between older children (0.287 +/- 0.101 liter/hr/kg) and adults. Inasmuch as the average steady-state serum drug concentration for a given daily maintenance dose is directly related to clearance rate, children less than 12 years of age may require a higher dosage of quinidine on a per kilogram of body weight basis. Proper selection of quinidine dosage, careful adjustment of dosage according to age, and regular monitoring of drug response and serum drug concentration are essential steps to a rational management of quinidine therapy in children.

Administration, Oral↗
PubMed1981

Alpha adrenoceptor blockade with oral prazosin.

alpha-Adrenoceptor blockade after placebo and 5-mg oral doses of prazosin was assessed in five normal subjects over a range of phenylephrine infusion rates. Systolic blood pressure during a 400-microgram/min infusion of phenylephrine at 3 hr after placebo or prazosin was 172.8 +/- 6.2 and 108.7 +/- 4.4 mm Hg (p less than 0.05). The phenylephrine effects were blocked from 1 hr to at least 7 hr after prazosin. The drug-sensitivity ratio, an indicator of alpha-adrenoceptor blockade, before prazosin was 1.1, rising to 4 at 1 hr, 4.9 at 3 hr, 5.7 at 5 hr, and 4 at 7 hr after oral prazosin. The highest prazosin plasma concentration after a 5-mg oral dose was 29.3 +/- 6.6 ng/ml. It occurred 1 hr after prazosin. The elimination half-life was 2.9 +/- 0.3 hr. After oral prazosin the alpha-adrenoceptor blockade response did not correlate with prazosin plasma concentration.

Adrenergic alpha-Antagonists↗
PubMed1980

Tissue distribution kinetics of tetraethylammonium ion in the rat.

Tissue distribution kinetics of tetraethylammonium (TEA) ion in rats were studied following both constant-rate intravenous infusion and rapid intravenous injection of the drug. At a steady-state plasma concentration of 0.2 microgram/ml, the tissue-to-plasma (T/P) concentration ratio of the kidneys, liver, heart, gut, and lungs exceeded 1, indicating that TEA is localized in these tissues. In vitro tissue homogenate binding and slice uptake experiments provided no evidence of TEA binding to tissue constitutents, suggesting that the high T/P concentration gradient is due to an active transport process. The maximum concentration of TEA in all tissues occured with 5-15 min after rapid injection of a 2-mg dose. Except for the liver, the subsequent decline of TEA concentration in various tissues over a 5-hr period was slow compared to that in plasma. Consequently, the T/P ratio of liver and kidney remained relatively constant, while those of the other tissues increased continually with time. These features of TEA tissue distribution kinetics can be predicted by a physiologically based pharmacokinetic model which incorporates both active and passive transport processes for the passage of TEA between blood and the tissue mass.

Animals↗
PubMed1980

Pharmacokinetics of hydralazine and its acid-labile hydrazone metabolites in relation to acetylator phenotype.

The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t 1/2 beta) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given orally, the area under the plasma concentration-time curve (AUC) and a systemic availability (theta) in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed theta in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acid-labile metabolites was similar to the t 1/2 beta of H. The AUCs for metabolies were 4--12 times larger than for the parent drug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective of routes of administration or the acetylator status.

Acetylation↗
PubMed1980

The effect of concurrent oral administration of propranolol and disopyramide on cardiac function in healthy men.

Sixteen healthy men were evaluated for left ventricular performance changes and beta-blockade after therapeutic oral doses of disopyramide and propranolol administered alone and concurrently. The volunteers were randomly assigned to receive one of two drug treatment regimens that differed in the sequence and duration of administration of the drugs. Left ventricular function was assessed by echocardiographically determined ejection fraction (EF) and systolic time intervals. Beta-blockade was assessed by changes in exercise heart rate. Both disopyramide and propranolol exhibited negative inotropic activity, as evidenced by significant, although clinically inconsequential, decreases in EF and increases in the ratio of preejection period to left ventricular ejection time. The negative inotropic effects of a single 200-mg dose of disopyramide and an 80-mg dose of propranolol were comparable, while chronic disopyramide therapy (200 mg every 6 hours for 1 week) had a greater negative inotropic effect than chronic propranolol therapy (80 mg every 8 hours for 1 week). Only propranolol had beta-adrenoceptor blocking activity. When the drugs were administered concurrently, the negative inotropic effects of oral propranolol and disopyramide were neither additive nor synergistic.

Administration, Oral↗
PubMed1978

Theophylline bioavailability following chronic dosing of an elixir and two solid dosage forms.

Theophylline bioavailability following chronic dosing of an elixir and two commercial tablet formulations (I and II) relative to an acute dose of elixir was evaluated in healthy volunteers. Both tablet formulations contained ephedrine. In addition, Tablet I contained hydroxyzine hydrochloride, and Tablet II contained phenobarbital. The mean area under the serum concentration-time curve (AUC) calculated either from time 0 leads to infinity for a single dose or over one dosing interval after repetitive doses was the highest after chronic administration of the elixir. The AUC after chronic elixir, in fact, was statistically different from the values after acute elixir (p less than 0.05) and Tablet II (p less than 0.05). There was, however, a large variation in the elimination half-life among the four theophylline treatments. The mean t 1/2 was the longest after chronic elixir followed by Tablet I, Tablet II, and acute elixir. The AUC values for the four treatments, when corrected for differences in t 1/2, were no longer significantly different, indicating that the extent of theophylline absorption was essentially the same from all three tested products. The time to peak and the peak serum concentration also did not differ among treatments. The prolongation in t 1/2 following chronic treatment with the elixir and its subsequent shortening during tablet administration suggest an initial inhibition followed by induction of theophylline metabolism. The changes may be due to the prolonged treatment with theophylline itself or the other drug ingredients in the dosage form.

Adult↗
PubMed1978

Separation and identification of impurities in parenteral methotrexate dosage forms.

Eleven lots of parenteral methotrexate (MTX) dosage forms from two manufactures have been analyzed and found to be 93.4% +/- 2.1% (SD) pure by a new procedure employing a DEAE-cellulose column adapted for high performance liquid chromatography instrumentation. In addition to 4-amino-10-methylpteroic acid and N10-methylpteroylglutamic acid, which were previously identified contaminants, and benzyl alcohol, which was added as a preservative, we have also isolated and identified 2,4-diamino-6-methylpteridine, 2,4-diamino-6-bromomethylpteridine, and p-methylaminobenzoic acid. Another impurity has tentatively been identified as 4-amino-10-methylpteroic acid amide. The individual impurities vary from 0.1% to 4.8% of the ultraviolet absorbing material which elutes from the column. Additional impurities were detected by gas chromatography-mass spectrometry. Since "high-dose" therapy may involve the administration of up to 20 g of MTX/day, the effect of the impurities present in these dosage forms on the course of the patient's therapy should be determined.

Chromatography, High Pressure Liquid↗
PubMed1977

Bioavailability of digoxin-hydroquinone complex: a new oral digoxin formulation.

A new oral digoxin formulation, a digoxin-hydroquinone complex (99% dissolution at 5 min), was evaluated in 12 healthy human volunteers with reference to bioavailability and extent and time of peak serum digoxin levels. This preparation was compared with a commercial digoxin tablet (26% dissolution at 5 min), digoxin elixir, and a parenteral digoxin solution. Bioavailability was assessed by the 24-hr area under the serum digoxin-time curve and 48-hr digoxin excretion in urine. The bioavailability of the complex was similar to that of the elixir but not statistically different from that of the tablet. The tablet was less bioavailable than the elixir. There was less interindividual variation in bioavailability with the complex than with the elixir. Peak serum digoxin levels were higher with the complex than the tablet and were achieved more quickly.

Administration, Oral↗