Aspirin pharmacokinetics in migraine. The effect of metoclopramide.
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Adult↗
Biomedical subjects
F Bochner
Publications and source records attributed to F Bochner.
Aspirin kinetics and platelet aggregation in man.
Our aims were (1) to determine the effect of six commercially available aspirin (ASA) preparations on in vitro platelet aggregation, and (2) to relate changes in platelet function to ASA kinetics. Each of six subjects took a single dose of one of the following preparations--600 mg Asproclear, 600 mg Bufferin, 600 mg Bi-prin, 600 mg compressed ASA, 650 mg Ecotrin, or 650 mg S.R.A.--in random order every 3 wk. Venous blood was drawn before and at 2, 4, 6, and 24 hr after ASA dosage to measure platelet aggregation in response to collagen and adenosine diphosphate and, at more frequent intervals, to characterize ASA kinetics. Asproclear, Bufferin, Bi-prin, and compressed ASA yielded peak plasma ASA levels of 28 to 56 mumol/l (5 to 10 mg/l) within 15 to 60 min and peak salicylic acid (SA) levels of 72 to 290 mumol/l (10 to 40 mg/l) within 2 hr. Ecotrin and S.R.A. yielded plasma SA levels of 14 to 87 mumol/l (2-12 mg/l) within 4 to 24 hr and no measurable ASA at any time after dosing. Platelet aggregation was inhibited to an equal extent by all preparations. The time course for this inhibition was the same for all preparations but Ecotrin (which led to a more delayed effect). There was significant recovery of collagen-induced platelet aggregation at 24 hr with all preparations but Ecotrin. With Ecotrin and S.R.A. there was inhibition of platelet aggregation in the absence of measurable circulating ASA. We postulate that this was due to acetylation of cyclooxygenase in the portal circulation and that inhibition of peripheral cyclooxygenase may be spared.
Adult↗
Lack of interaction between ranitidine and phenytoin.
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Drug Interactions↗
Therapeutic drug monitoring: a survey of sub- and supra-therapeutic serum drug levels in a large teaching hospital.
One thousand five hundred serum drug levels lying outside the defined therapeutic range have been followed up by the clinical pharmacology service at the Royal Adelaide Hospital over a thirteen month period. It was found that digoxin, phenytoin and theophylline were the most frequently monitored drugs. Blood levels outside the therapeutic range tended to be on the high side with digoxin, but were usually sub-therapeutic for the other two. Drug related toxicity was observed in 11.2 percent of those with a high serum level. Several potential drug interacting situations were also noted during the study. The value of therapeutic drug monitoring, to maximise efficacy of therapy and minimise side effects, is stressed. However, correct blood sampling, based on a knowledge of the clinical pharmacology and pharmacokinetics of the drug, must be performed in order to obtain optimal benefit from this exercise.
Carbamazepine↗
Plasma levels of aspirin following effervescent and enteric coated tablets, and their effect on platelet function.
Single doses of effervescent tablets (1200 mg) and enteric coated (EC) tablets (1300 mg and 650 mg) of acetylsalicylic acid (aspirin, ASA) were given to healthy volunteers in random order. Plasma ASA and salicylic acid (SA) levels were measured and concurrent in vitro measurements of the volunteers' platelet aggregation were carried out. The effervescent preparation resulted in peak ASA concentrations of 17-40 mg/l, achieved 20 to 30 min after a 1200 mg dose, whereas peak ASA levels of 0.01-0.37 mg/l were observed 4-6 h after a 650 mg dose of the EC preparation. With all the aggregating agents that were added to the test system maximum inhibition of platelet aggregation (about 50% of pre dose levels) was seen 1.0 h after the effervescent ASA dose, and persisted to at least 24 h, but with the EC preparation not until 24 h, at which time the degree of inhibition was also about 50% of pre-dose levels. A 1.0 g dose of sodium salicylate had no effect on in vitro platelet function. It was concluded that mean plasma levels of ASA of less than 0.25 mg/l are sufficient to depress aggregation by approximately 50%. A low dose of ASA taken daily either as effervescent ASA or EC ASA, significantly inhibits platelet aggregation and so may reduce the risk of ischaemic episodes in susceptible patients.
Adult↗
Urinary excretion of aspirin.
Six human volunteers were each given single oral doses of aspirin (ASA) ranging from 300-1,500 mg. The unchanged ASA excreted in the urine was proportional to dose and urinary pH. The mean percent (+/- s.d.) of dose excreted was 1.9 +/- 0.67. The clearance for ASA was 1.42 +/- 0.28 1/h. The rate of in vitro hydrolysis of ASA to salicylic acid in urine at 37 degrees C was 4 micrograms/min for an initial ASA concentration of 7.5 mg in 100 ml human urine.
Adult↗
In vivo and in vitro studies on the binding of salicylate to human plasma proteins: evidence for one type of binding site.
In vivo and in vitro binding of salicylate to plasma proteins was studied by ultrafiltration at room temperature. The nonlinearity of the Scatchard and Klotz plots were explained by the presence of lipid-soluble substances in plasma. Delipidation of plasma resulted in changes of the binding characteristics of plasma in that more moles of salicylate could be bound per mole of protein. This changed the appearances of the Scatchard and Klotz plots so that a much larger range of salicylate concentration could be accommodated by the linear portion of the graphs. The equilibrium constant for the in vitro salicylate binding was identical for the delipidated and untreated plasma. However, the in vivo binding constant for salicylate in plasma was higher than the in vitro binding constant.
Adult↗
Cimetidine interaction with phenytoin.
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Adult↗
Hallucinogenic drug induced vasculitis.
A case of malignant hypertension in a 20-year-old man who self-administered various hallucinogenic drugs is described. Renal angiography showed arteritic changes with aneurysms in renal vessels and focal renal cortical infarction. A dramatic response in terms of resolution of arteritis occurred with prednisone therapy. The impressive use of minoxidil and labetalol in the initial control of the hypertension is also demonstrated.
Adolescent↗
Single-dose pharmacokinetics of metoclopramide.
The time courses of plasma metoclopramide concentrations were followed in six subjects after oral and intravenous single dose administration. Plasma concentration-time data following i. v. administration in each subject were found to fit a two compartment model with a mean terminal half-life of 4.55 h +/- 0.80 h and a mean distribution half-time of 0.35 h +/- 0.09 h. Volumes of distribution were high (3.43 +/- 1.181 . kg-1), and clearances (0.53 +/- 0.191 . kg-1 h-1) approached liver plasma flow. This suggests that metoclopramide occurs at higher concentrations in tissues than in plasma, and that its clearance is probably limited by liver blood flow rather than liver metabolic capacity. The postabsorption decline in metoclopramide plasma levels after oral administration was also biexponential in each subject. The terminal half-life was 5.17 h +/- 0.98 h. Mean volume of distribution and mean clearance were similar to intravenous values (after adjustment for bioavailability). Oral absorption was rapid with peak plasma concentrations being reached at a mean time of 0.93 h. A mean bioavailability of 0.77 was calculated for the six subjects, and it was postulated that this incomplete availability is due to a first-pass effect. The inter-individual variation in the degree of "first-pass' was considerable (0.47--1.14).
Administration, Oral↗
Salicylate metabolite kinetics after several salicylates.
Single oral doses of aspirin (ASA, 1,500 mg), sodium salicylate (NaSA, 1,500 mg, 1,200 mg), and salicyluric acid (SUA, 500 mg) were given to five subjects. Serial plasma and urine samples were collected for 24 hr (plasma) and up to 48 hr (urine); salicylic acid (SA), SUA, and gentisic acid (GA) were measured by high-pressure liquid chromatography. The plasma concentration/time profiles for SUA after ASA and NaSA were fitted to the empirical equation CpSUA = A-Bt-Ce-alpha t -- (A-C)e-beta t. Michaelis constants (Vm and Km) for the conversion of SA to SUA were calculated from the equation (formula see text), where Cl is the renal clearance of SUA, ke is the rate constant of elimination of SUA, CpSA is the plasma concentration of salicylic acid. The term Cl (formula see text) is the estimated rate of formation of SUA from SA at any time (t). The calculated values (mean +/- SD) of Vm, Km, and Kmf (Km in terms of unbound SA) were 43.4 +/- 10.1 mg SA/hr, 14.3 +/- 3.4 mg SA/l plasma, and 0.75 +/- 0.15 mg unbound SA/l plasma. The Vm values were in accord with those reported, but the value for Km was considerably lower. Renal clearances of SUA and GA were 340 +/- 51 and 65 +/- 10 ml/min.
Adult↗
Intraoperative pharmacokinetics of dexamethasone.
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Adult↗
Comparative bioavailability study of theophylline tablets marketed in Australasia.
Average peak concentrations of theophylline in plasma (range, 15 mumol/L) were not significantly different when Nuelin, Brondecon and Choledyl tablets were administered to healthy subjects. The fraction of the theophylline dose absorbed from these preparations was comparable (range, 0.82 to 0.90). In contrast, the absorption of theophylline was significantly different (P < 0.001) when the times to reach peak theophylline concentration were compared. Mean peak theophylline concentrations were achieved 1.5 hours after administration of either Nuelin or Brondecon tablets and nine hours after Choledyl administration. Nuelin and Brondecon are considered to be bioequivalent. Choledyl may be used when side effects caused by rapid theophylline absorption are to be avoided.
Absorption↗
Electron-capture gas chromatographic assay for metoclopramide in plasma.
An original electron-capture gas chromatographic assay has been developed for the quantiation of metoclopramide in human plasma. The method involves derivatization with heptafluorobutyryl imidazole after alkaline extraction, acid backwash, and a further alkaline extraction. Plasma levels of metoclopramide as low as 5 micrograms/l can be measured using 1 ml of plasma, and no interference from related substances or commonly prescribed drugs has been found. The percentage recovery of drug from plasma ranges from 88% to virtually 100%, and the between-run variation in the assay is 4.3%. The assay has been used for the study of metoclopramide pharmacokinetics in man following intravenous single-dose administration. The resultant plasma concentration vs. time curve was biexponential, with a terminal half-life of 5.0 h, and a distribution half-time of 0.3 h.
Acetylation↗
Measurement and pharmacokinetics of acetylsalicylic acid by a novel high performance liquid chromatographic assay.
Plasma acetylsalicylic acid and salicylic acid are assayed by a specific, rapid, and sensitive high performance liquid chromatographic procedure. The plasma samples are treated with physostigmine to inhibit esterase activity that otherwise will promote enzymatic hydrolysis of acetylsalicylic acid to salicylic acid. Conditions are chosen such that the total in vitro hydrolysis of acetylsalicylic acid is minimized to less than 5%. Plasma samples are deproteinated with methylcyanide. Acetylsalicylic acid and salicylic acid are separated by elution with a mixture of methanol, acetic acid, and water on a reversed-phase octadecyl silane column and detected by ultraviolet absorption. Quantitation is achieved by measuring absolute peak heights. Recovery and repeatability studies are good. No interference was observed when 50 drugs were also present in the various plasma samples. Concentrations of acetylsalicylic acid and salicylic acid can be obtained within 20 min of receipt of the blood specimens. Pharmacokinetic parameters obtained by this method after a single oral dose of 900 mg soluble, effervescent acetylsalicylic acid in normal healthy subjects suggest that absorption, distribution, and elimination of acetylsalicylic acid are rapidly occurring events.
Aspirin↗
High performance liquid chromatographic assay of dexamethasone in plasma and tissue.
Dexamethasone in plasma and in tissue is specifically quantitated by high performance liquid chromatography (ultraviolet detection at 254 nm) with an octadecyl silane reversed-phase chromatographic column employing peak-height ratio determination (internal standard, cyheptamide). The sample is first washed with heptane under alkaline conditions. The dexamethasone is then extracted from the washed sample with dichloromethane containing the internal standard. Dichloromethane is evaporated to dryness, and the concentrated extract is dissolved in tetrahydrofuran and then injected into a high performance liquid chromatograph. Dexamethasone and internal standard are eluted with a mixture of acetic acid, methanol, butanol, and water (11/19/30/440 by volume). Sensitivity limit is 10 ng, with linear response to at least 1.000 mg/liter plasma. Analytical recovery of dexamethasone from plasma is almost complete, and approximately 87% dexamethasone is recovered from brain tissue. Intra-assay precision (CV) is 1.07% (N = 11), and interassay precision is 1.38% (N = 5). No interference occurred in plasmas from patients treated with various drugs other than dexamethasone. Dexamethasone was estimated in plasma and in tumor tissue from patients on dexamethasone therapy.
Administration, Oral↗
Simultaneous liquid-chromatographic quantitation of salicylic acid, salicyluric acid, and gentisic acid in urine.
We have developed a specific and sensitive method for the determination of salicylic acid, salicyluric acid, and gentisic acid in urine. Any proteins present are precipitated with methyl cyanide. After centrifugation, an aliquot of the supernate is directly injected into an octadecyl silane reversed-phase chromatographic column, then eluted with a mixture of water, butanol, acetic acid, and sodium sulfate, and quantitated at 313 nm by ultraviolet detection according to peak-height ratios (with internal standard, o-methoxybenzoic acid) or peak heights (no internal standard). The method allows estimates within 25 min. Sensitivity was 0.2 mg/L for gentisic acid, and 0.5 mg/L for both salicyluric and salicylic acid (20-micro L injection volume); response was linear with concentration to at least 2.000 g/L for salicylic acid and metabolites. Analytical recovery of salicylic acid and metabolites from urine is complete. Intra-assay precision (coefficient of variation) is 5.52% at 7.5 mg/L for salicylic acid, 5.01% at 9.33 mg/L for salicyluric acid, and 3.07% at 7.96 mg/L for gentisic acid. Interassay precision is 7.32% at 7.51 mg/L for salicylic acid, 5.52% at 8.58 mg/L for salicyluric acid, and 3.97% at 8.32 mg/L for gentisic acid. We saw no significant interference in urine from patients being treated with various drugs other than aspirin.
Aspirin↗
Prednisolone pharmacokinetics in asthmatic patients.
Prednisolone serum levels have been measured by radio-immunoassay in 12 steroid-dependent asthmatic patients. Differences in prednisolone pharmacokinetics did not account for the variation in dose of prednisolone required to control asthma.
Adult↗