ORG 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man.

ORG 10172 is a heparinoid with mean molecular weight 6500 daltons. Intravenous bolus injections of ORG 10172 were compared with placebo and heparin injections in 91 separate studies in 83 healthy male subjects. 6400 units ORG 10172 produced a mean maximum change of 14.7 s in kaolin cephalin time (c.f. greater than 120 s for 5000 units heparin). Changes in prothrombin time were minimal (1.6 s for 6400 units ORG 10172 and 4.5 s after 5000 units heparin). A dose-related increase in bleeding time occurred after ORG 10172 and at high doses (greater than 3200 units) some secondary bleeding, which was never serious, occurred at between 1 and 4 h after incision. A dose-dependent reduction in ex vivo platelet adhesiveness was found at 10 min after ORG 10172 injection. ORG 10172 promoted a much smaller release of lipoprotein lipase as compared with heparin. The effect of ORG 10172 on plasma factor Xa activity (one measure of its action) was described by a biexponential decay with a mean distribution half-life of 2.34 (s.e. mean 0.16) h and mean disposition half-life of 17.6 (s.e. mean 1.1) h. It thus has a much longer duration of effect than heparin. There was a linear relationship of plasma anti-Xa response to increasing dose although there was some variability only partly explained by differences in body weight or surface area. ORG 10172 administration by bolus intravenous injection was well tolerated and there was no evidence of adverse effects on clinical chemistry or haematology tests.

Comparison of pharmacokinetic profiles of single and multiple doses of a slow release Oros oxprenolol delivery system in young normotensive and elderly hypertensive subjects.

Oxprenolol in an Oros 8/130 sustained release osmotic pump system (equivalent to 120 mg oxprenolol hydrochloride in a conventional formulation and releasing 8 mg h-1) was given to eight normal young subjects (mean age 23 years) and eight elderly hypertensive patients (mean age 77 years). The plasma concentration-time profiles of oxprenolol were determined over 32 h using gas liquid chromatography after the initial dose and following seven doses. The elderly patients had a significantly higher AUC and maximum plasma oxprenolol concentration following both the first and final doses studied. It is unlikely that this difference is due to a prolonged absorption phase in the elderly patients. Reduced drug clearance seems the most probable explanation.

The effects of domperidone on the absorption of levodopa in normal subjects.

The effect of simultaneous oral administration of 20, 40, or 80 mg domperidone on the pharmacokinetics of an oral 500 mg dose of levodopa was studied in eight normal women. No significant differences in maximum plasma levodopa concentration, the time of its attainment, or the area under the plasma levodopa concentration versus time profile occurred. Domperidone significantly reduced the incidence of adverse gastrointestinal effects due to levodopa administration.

Effects of single and multiple doses of ketoconazole on adrenal function in normal subjects.

The plasma cortisol response to 0.25 mg tetracosactrin given by intramuscular injection was suppressed by nine oral doses of 200 mg ketoconazole given 12 hourly to nine normal female subjects. No effect was noted following a single 200 mg oral dose of ketoconazole. This suppressive effect was reversible within at least 5 days of discontinuation of ketoconazole.

High-performance liquid chromatographic assay for simultaneous estimation of aminoglutethimide and acetylaminoglutethimide in biological fluids.

A simple rapid high-performance liquid chromatographic assay for simultaneous estimation of aminoglutethimide and its acetylated metabolite acetylamidoglutethimide in plasma, saliva, and urine is described. This assay is suitable for pharmacokinetic studies in normal subjects and patients receiving other medication in addition to aminoglutethimide.

Pharmacokinetic investigation of the absorption of oxprenolol from Oros delivery systems in healthy volunteers: comparison of in vivo and in vitro drug release.

The absorption kinetics of oxprenolol have been investigated in eight healthy volunteers after single dosing with 16/260 Oros drug delivery systems. Oxprenolol disposition kinetics in individual subjects were estimated from intravenous dose data. Loo-Riegelman analysis of the plasma concentration data indicated an extended duration of drug absorption for the Oros system. Initially, the in vivo absorption rate was similar to the in vitro release rate but after 5-6 h it slowed perceptibly. However, at later times similar in vivo and in vitro rates were again observed. The absolute bioavailabilities for prototype and clinical trial systems were shown to be similar, at approximately 42%, and no significant differences in plasma profiles or pharmacokinetic constants were detected between the two Oros forms. A comparison of plasma concentration data in seven subjects who received the prototype system on two occasions in separate studies indicated a consistent level of drug absorption from this preparation. Approximately 10-15% of the administered dose was found in Oros systems recovered from faeces. The quantity of drug remaining was poorly correlated with the observed areas under the plasma concentration-time curve.

Pharmacokinetic observations on piroxicam in young adult, middle-aged and elderly patients.

Nineteen out of 21 patients with painful conditions of the locomotor system aged between 27 and 94 years completed a study in which they received 20 mg piroxicam daily for 14 days. Plasma piroxicam concentrations were estimated by high performance liquid chromatography. Pharmacokinetic analysis of the data showed the half-life and systemic clearance of piroxicam to be unaffected by age. The apparent volume of distribution in older patients was higher than that of younger subjects. Multiple regression analysis showed that creatinine clearance and plasma albumin concentration had insignificant effects on the systemic piroxicam clearance. Although improvement in joint pain and stiffness occurred during the 2 week study period, this could not be correlated with plasma piroxicam concentration.

Pharmacokinetics and bioavailability of sultamicillin estimated by high performance liquid chromatography.

Sultamicillin is an orally absorbed double ester of sulbactam (penicillanic acid sulphone, a semisynthetic inhibitor of the beta-lactamases of many Gram-positive and Gram-negative species) and ampicillin. First-pass hydrolysis of this prodrug liberates equimolar proportions of sulbactam in plasma, saliva and urine is described and was used to determine the absolute bioavailability of sulbactam and ampicillin from sultamicillin in six normal male volunteers who each received a single 750 mg oral dose of sultamicillin or an iv dose of the equivalent amounts of ampicillin (441 mg) and sulbactam (294 mg). Treatments were given in random order with not less than four days intervening. The mean peak plasma concentrations and time to peak of sulbactam and ampicillin following the 750 mg oral half lives, systemic and renal clearances for sulbactam and ampicillin were similar. The bioavailability for both drugs from sultamicillin as estimated from both plasma and urine pharmacokinetics was better than 80%. We conclude that sultamicillin is an extremely efficient prodrug for ampicillin and sulbactam and that the HPLC assay method is accurate, rapid and easier to perform than the differential microbiological assay.

Effect of pirprofen on glibenclamide kinetics and response.

Pirprofen (a new non-steroidal anti-inflammatory agent), 200 mg 8 hourly, or placebo was administered orally to eight normal volunteers to investigate its effect on the pharmacokinetics and glucose and insulin responses after 1 mg i.v. glibenclamide. No significant changes were produced in these measures and in vitro studies showed no displacement of glibenclamide by pirprofen from plasma protein binding.

Pharmacokinetics of intravenous glibenclamide investigated by a high performance liquid chromatographic assay.

A simple high performance liquid chromatographic assay for the determination of plasma glibenclamide concentrations is described. This resolved glibenclamide from normal plasma constituents. The calibration curve of the assay was linear over the range 10-500 microgram/l and the minimum level of detection was 2 microgram/l. Within-assay coefficients of variation were 11.6% (20 microgram/l); 5.3% (50 microgram/l); 6.8% (100 microgram/l); between-assay coefficients of variation were 8.4% (20 microgram/l); 4.7% (50 microgram/l) and 7.4% (100 microgram/l). The assay was used to study the pharmacokinetics of a 1 mg intravenous dose of glibenclamide in eight normal subjects. The mean half-life was found to be 1.47 +/- 0.42 h (SD) and no evidence for a non-linear beta-phase or slowly equilibrating 'deep' compartment was found although this could not be rigorously excluded. The mean systemic drug clearance was 78 +/- 29 ml X h-1 X kg-1 and the apparent volume of distribution in the beta-phase was 155 +/- 44 ml/kg. The median time of maximum response of plasma immunoreactive insulin was 25 min and the median time of maximum blood glucose response was 53 min. No correlation could be found between the pharmacokinetics of glibenclamide and these responses in fasted normal individuals.

Pharmacokinetics of single doses of sulphinpyrazone and its major metabolites in plasma and urine.

1 High pressure liquid chromatographic assays for the estimation of sulphinpyrazone and its sulphide, sulphone and p-hydroxy metabolites in plasma and urine are described. 2 Five normal volunteers received 200 mg and 400 mg sulphinpyrazone orally. Sulphinpyrazone was rapidly absorbed and eliminated with a half-life of approximately 4 h irrespective of dose. Peak plasma concentrations and area under the plasma concentration-time curves (AUC) were consistent with linear pharmacokinetic behaviour. 3 Plasma concentrations of the sulphone were low and peaked before those of the sulphide; its mean half-life was 3.1 h. The sulphide, which may be the sulphinpyrazone metabolite with activity on platelets, was eliminated with a mean half-life of 13.4 h. The AUC increases with dose of both metabolites suggested non-linearity. 4 Approximately 45-50% of the administered dose was eliminated in the urine as unchanged drug or as sulphone or p-hydroxy-sulphinpyrazone. The sulphide metabolite was not detected in the urine. The renal clearance of sulphinpyrazone was approximately 18 ml min-1 and that for the sulphone was similar. Sigma minus plots of the urinary excretion yielded half-lives of 3.5 h for the sulphone and 1 h for p-hydroxy-sulphinpyrazone.

Bioavailability of phenylbutazone from a new enteric-coated formulation with superior dissolution characteristics.

The bioavailability of an improved formulation of enteric-coated phenylbutazone with faster dissolution, more consistent in vitro rate of drug release and improved stability was compared in 8 normal subjects at doses of 100 and 200 mg with commercially available Butacote. Phenylbutazone was more rapidly absorbed from the new formulation and higher plasma concentrations were achieved at shorter intervals after dosing. Drug elimination rate was unaffected by reformulation and despite faster absorption the total amounts of drug reaching the circulation from the new and commercial products were similar. It was concluded that replacing Butacote by the new formulation would provide the same therapeutic benefit.

Effect of cimetidine on the absorption and efficacy of orally administered furosemide.

In six normal subjects who received single oral doses of 400 mg cimetidine and 40 mg furosemide, the area under the furosemide plasma concentration-time curve was increased in two subjects by less than 50%, in two by 59% and 75%, and remained unchanged in two: overall the mean increase of approximately one-third achieved statistical significance. This increase was not accompanied by any significant effects on other pharmacokinetic parameters or urine volume, sodium or potassium excretion during the 8 h subsequent to drug administration. Furosemide produced no effects on cimetidine pharmacokinetics. In another group of subjects, administration of 1.0 g cimetidine/day in divided doses before dosing with 40 mg furosemide produced no significant effects on furosemide plasma levels or in its effects on urinary water and electrolyte excretion.

Plasma mexiletine concentrations following combined oral and intramuscular administration.

Mexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil--for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75-2 microgram/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.

Plasma and salivary pharmacokinetics of caffeine in man.

Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163 +/- 0.081 h-1 for 50 mg and 0.098 +/- 0.027 h-1 for 750 mg. The total body clearance was unaffected by dose and was 0.98 +/- 0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74 +/- 0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.

Effect of cimetidine on the absorption of orally administered tetracycline.

1 Six healthy female subjects received orally two 250 mg tetracycline tablets either with 400 mg cimetidine or placebo. In a separate experiment six healthy female volunteers received 500 mg tetracycline as a suspension on the fifth day of a 6 day regime of 400 mg cimetidine or placebo, 8 hourly and at bedtime. 500 mg tetracycline as tablets was also given with cimetidine only. 2 Following a single dose of cimetidine the mean peak tetracycline plasma concentration was significantly reduced by 1.2 microgram/ml and the area under the plasma concentration, time curve was decreased by 40%. The 72 h urinary tetracycline excretion was diminished by approximately 30%. 3 Tetracycline had no effect on the plasma concentration, time profile of cimetidine. 4 Administration of 400 mg cimetidine 8 hourly and at night for 6 days and dosing with 500 mg tetracycline as tablets or suspension on the fifth day produced no alteration in tetracycline kinetics. 5 It was concluded that under clinical circumstances it is unlikely that cimetidine produces a clinically significant alteration in tetracycline absorption or disposition. 6 The bioavailability of tetracycline from tablets and suspension was found to be similar (31.2% and 36.9% of the dose excreted in the urine over 72 h). 7 The mean renal clearance of tetracycline was 83.8 ml/min (95% confidence interval +/- 9.2 ml/min) and was unaltered by cimetidine treatment.