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Evans, Gwyn H.; Shand, David G.
doi: 10.1002/cpt1973144part1487pmid: 4723255
In 6 normal volunteers, a twofold accumulation of propranolol in the blood was observed during chronic oral administration of 80 mg every 6 hours that was unpredicted on the basis of the drug's half‐life. No accumulation occurred in 2 subjects given 20 mg intravenously every 6 hours. The observed drug accumulation resulted from two mechanisms. During administration of the first dose an avid hepatic extraction process became saturated after removal of about 30 mg and remained saturated during the dosage interval. This resulted in a 60% increase in the amount of drug reaching the systemic circulation at steady state compared to that after a single dose. It is suggested that the avid hepatic extraction is a result of high‐affinity drug binding and that the increase in availability is due to saturation of this binding site. In addition, the increase in drug availability was sufficient to partially saturate drug metabolism and decrease systemiC drug clearance, resulting in a 44% increase in drug half‐life. These data were supported by the finding that during steady state folloWing 6 hourly oral propranolol administration to 7 subjects, plasma levels were proportional to the dose up to 160 mg per day, suggesting first‐order drug elimination in the presence of a saturated high affinity binding site in the liver. An average of between 160 and 320 mg per day metabolism becomes nonlinear, resulting in a disproportionate increase in plasma concentrations. These studies indicate that saturable hepatic tissue binding, as well as safurable metabolism, can result in nonlinear kinetics of drug disposition.
Evans, Gwyn H; Shand, David G.
doi: 10.1002/cpt1973144part1494pmid: 4723256
Plasma binding of propranolol has been measured at therapeutic concentrations in 6 subjects in whom steady‐state blood concentrations and half‐life had been measured during chronic oral administration of 80 mg every 6 hours. Neither steady‐state blood concentrations nor drug clearance (Cl**) was related to binding of drug in the blood. Volume of distribution (Vdβ), however, increased as the fraction of free drug in the blood (fb) increased, such that the volume of distribution of free drug (Vdp/fb) was relatively constant. Drug half‐life was proportional to fb/Cl** since it was a function of both Vdp and clearance that varied independently. These data show that propranolol can be classified as a drug whose hepatic elimination is not restricted to the free drug in the circulation, so that binding to elements in the blood accelerates its elimination rate by acting as a carrier system from the tissues to its site of elimination and that this occurs without alteration drug clearance or steady‐state total blood concentrations.
Johnstone, Robert E.; Reier, Charles E.
doi: 10.1002/cpt1973144part1501pmid: 4723257
Six healthy subjects received ethanol 0.35, 0.70, and 1.05 ml per kilogram intravenously in 1 hour, causing average blood ethanol concentrations of 40, 99, and 121 mg per milliliter, respectively. Resting ventilatory minute volume (VE) and end tidal carbon dioxide tension (PACO2) were inconsistently affected. The ventilatory response to CO1 was depressed in a dose‐dependent manner. The PACO2 at a VE of 20 I per minute was 3.9 torr greater than control after the 1.05 ml per kilogram dosage. Respiratory exchange ratio decreased from 0.779 to 0.709 1 hour after the 1.05 ml per kilogram infusion. Vital capacity decreased from 5.42 to 5.09 1, and expiratory reserve volume decreased from 1.14 to 0.9311 hour following this dosage. Irregular ventilatory patterns with transient inspiratory and expiratory apnea were observed frequently following the 0.70 and 1.05 ml per kilogram dosages.
Mitenko, Paul A.; Ogilvie, Richard I.
doi: 10.1002/cpt1973144part1509pmid: 4723258
Plasma theophylline concentrations were measured after single intravenous infusions of aminophylline to asthmatic patients and normal volunteers. Using two‐compartment kinetic analysis, no basic differences in drug disposition were found. For the 16 subiects studied the overall mean plasma clearance rate was 0.0719 I per kilogram per hour, and overall mean beta or slow disposition constant was 0.159 hr−1, corresponding to a plasma half‐time of 4.36 hr. This information should be useful in determining precise dosage requirements for theophylline in clinical situations.
Breckenridge, A.; Orme, M. L'E.; Davies, L.; Thorgeirsson, S. S.; Davies, D. S.
doi: 10.1002/cpt1973144part1514pmid: 4723259
Administration of qUinalbarbitone, 100 mg nightly, caused a fall in steady‐state plasma warfarin concentration ranging from 5% to 64.5% in 6 patients. There was no correlation between the extent of this fall and either the plasma concentration of quinalbarbitone or the initial rate of warfarin metabolism. Increasing the dose of qUinalbarbitone to 200 mg nightly (2 patients) and 300 mg nightly (1 patient) permitted a study of the relationship between dose and degree of induction. By administration of varying doses of 4 inducing agents to rats and constructing a dose‐response curve, it was shown that phenobarbitone was a more potent inducing agent than quinalbarbitone, amylobarbitone, or antipyrine. Possible reasons for this include the longer plasma half‐life of phenobarbitone and the higher liver/plasma drug ratio. These data suggest that more information about the indUCing ability of drugs in man and animals can be derived by performing enzyme induction studies at several rather than at a single dose level.
Atkinson, Arthur J.; Shaw, John M.
doi: 10.1002/cpt1973144part1521pmid: 4198768
Sequential determinations of plasma diphenylhydantoin (DPH) concentration in a patient with DPH toxicity have been used to study its dose‐dependent elimination kinetics. A pharmacokinetic model has been proposed for DPH that provides estimates of the apparent distribution volume, and characterizes the elimination of this drug in terms of a maximal excretory rate and apparent Michaelis‐Menten constant. This three‐parameter model has been used to illustrate a retrospective way of evaluating some possible causes of DPH toxicity in this patient.
doi: 10.1002/cpt1973144part1529pmid: 4723260
In a comprehensive drug monitoring program adverse reactions to diphenylhydantoin (DPH) were recorded in 11.4% of 88 patients with an admission serum albumin lower than 3.0 gm per 100 ml1'eceiving DPH and in 3.8% of 234 patients with a normal serum albumin receiving DPH. This difference was sustained after taking into account factors such as dosage, age, sex, primary diagnosis, and admission blood urea nitrogen. It is suggested that hypoalbuminemic patients have increased circulating levels of unbound DPH that increases the risk of toxicity to this drug.
Roth, Walton T.; Tinklenberg, Jared R.; Kopell, Bert S.; Hollister, Leo E.
doi: 10.1002/cpt1973144part1533pmid: 4723261
The EKG was continuously recorded in 10 normal subjects during marihuana and placebo administration. NIMH marihuana was administered in cigarettes calibrated to a delta‐9‐tetrahydrocannabinol content of 20 mg. Automated methods of data analysis were used to scan the EKG records for cardiac arrhythmias and to plot graphs of pulse rate and average T wave amplitude computed every 20 seconds over sessions lasting from 2 to 4 hours. Only 5 ventricular premature contractions occurred in all of the sessions; they were not related to marihuana intoxication. The marihuana‐induced tachycardia had a mean of 127.6 beats per minute with a latency of 17.8 minutes from the onset of smoking to maximum tachycardia. T wave changes were slight and did not correspond to other effects of marihuana. We suggest that syncopal episodes associated with marihuana intoxication are not associated with cardiac arrhythmias, but rather with orthostatic or vasovagal reactions combined with inhibition of compensatory vascular reflexes.
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