The pharmacokinetics of high-dose busulphan was studied in adult patients with acute myeloblastic leukaemia after oral doses of 1 mg.kg-1 every 6 h for 4 days. The mean steady-state plasma concentration was 1080 ng/ml-1 during the treatment. Individual steady-state concentrations after the last dose on average were 32% lower than those predicted from total AUC measurements following the first dose. Mean elimination half-life in plasma was 2.3 h after the last dose and 3.4 h after the first dose which suggests that busulfan may increase its own metabolic rate on repeated treatment. The cerebrospinal fluid/plasma concentration ratio of busulphan was 1.3. Busulphan showed insignificant protein binding in plasma (7.4%). About 2% of the dose was excreted unchanged in the urine. For the first time sulpholane, 3-hydroxysulpholane and tetrahydrothiophene 1-oxide were identified as urinary metabolites of busulphan in man.

No abstract

The pharmacokinetics of sulpiride was studied in 6 healthy volunteers after intravenous and oral (tablets) administration of 100 mg. An open two- and in two subjects a three-compartment model was applied following intravenous administration. The average total distribution volume during the terminal slope was 2.72 +/- 0.66 l/kg and total systemic clearance was 415 +/- 84 ml/min. The serum half-life of the terminal slope following intravenous administration averaged 5.3 h (range 3.7--7.1 h) according to the two-compartment model. In two subjects the half-lives were 11.0 and 13.9 h when the three-compartment model was applied. Determinations of urinary excretion rates of unchanged sulpiride indicated a half-life of 7.15 h. Following intravenous administration, 70 +/- 9% of the dose was recovered unchanged in urine within 36 h; the mean renal clearance was 310 +/- 91 ml/min. Sulpiride was absorbed slowly, with peak concentrations appearing between 3 and 6 h after oral administration. The recovery of unchanged drug in urine following oral administration was 15 +/- 5% of the dose, with a mean renal clearance of 223 +/- 47 ml/min. The bioavailability determined from combined plasma and urine data was only 27 +/- 9%. The low bioavailability was probably due to incomplete absorption.

Fluoride (3 mg) was administered as a continous intravenous infusion during 30 min to 6 healthy subjects. Plasma concentrations and urinary excretion of fluoride in these experiments were compared with those obtained following oral administration of 2.82 mg, 4.50 mg, 5.64 mg, and 9.40 mg in the form of tablets and capsules. There were large day-to-day variations in the renal clearance of fluoride. This was shown to be due to differences in the urinary flow, an increase in flow causing an increase in renal clearance. The mean value of renal clearance from all experiments was 66.2 +/- 27.8 (SD; n = 16) ml/min. The extrarenal clearance, suggested to represent mainly the clearance to the bone pool, showed less interindividual variation: mean 110.3 +/- 32.3 (SD; n = 6) ml/min; the fraction remaining in the bone pool was highly consistent: 0.579 +/- 0.049 (SD; n = 6). When apparrent bioavailability was calculated from plasma and from urinary data, there was a great intra- and intersubject variation, as well as poor agreement between the two methods of calculations. This was found to be due to the day-to-day variation in renal clearance, which, in turn, varied with urinary flow. By use of equations that corrected for these variations, it was found that the bioavailability of sodium fluoride tablets is approximately 100%.

The bioavailability of fluoride (F) from NaF and Na₂PO₃F dentifrices was studied in detail in young volunteers. The method used was based on a comparison of plasma and urinary data obtained following intravenous administration of a single 3-mg dose F and ingestion of 6 g (6 mg F) of two different F dentifrices on three separate occasions. The plasma data indicated a higher degree of F bioavailability from the NaF dentifrice (111 ± 13%, SD, n = 4) as compared with theNa₂P0₃F dentifrice (96 ± 16%, SD, n = 4). Since the absorption of F from the F dentifrices was essentially total it is concluded that F dentifrices may play an important part in the daily exposure of children to F.

The new levodopa/carbidopa microtablets had a pharmacokinetic profile that would allow for a convenient switch of therapy from standard tablets. Frequent dose administration of levodopa/carbidopa microtablets with an electronic dose dispenser might offer an optimal oral drug delivery in Parkinson disease.

The effect of milk products on the gastrointestinal absorption of fluoride from sodium fluoride tablets was studied in five healthy subjects. Two different diets were tested: (1) 250 ml standardized milk (3% fat) and (2) 500 ml of milk, 3 pieces of white bread with cheese and 150 ml of yoghurt. The 100% bioavailability of sodium fluoride tablets during fasting was greatly decreased by coadministration of milk products: with Diet 1 the absolute bioavailability calculated from combined plasma and urine data was in the range 50--79% and with Diet 2 it ranged from 50--71%. It is suggested that the decreased bioavailability produced by dairy products should be taken into account when establishing flouride dosage regimens for prophylaxis of caries.

Five healthy subjects were each given fluoride 3.0 mg (F) as sodium fluoride tablets on two occasions - during production of acid urine, induced by giving NH4Cl, and during production of alkaline urine obtained by giving NaHCO3. Frequent plasma and urine samples were taken up to 12 h and were analyzed with a F- sensitive electrode. Control experiments without F administrations were also performed to permit calculation of net F concentration in plasma and urine. The urine F excretion was lower during acid than alkaline diuresis. Pharmacokinetic analysis of the net plasma F concentrations showed that the apparent plasma half-life of F was longer when urine was acid (4.3 +/- 0.6h: SD; n = 5) than when it was alkaline (2.4 +/- 0.4h). This could be explained by changes in the renal clearance of F, which was always lower with an acid (61.5 +/- 8.1 ml/min) than an alkaline (97.8 +/- 10.4 ml/min) urine. The apparent extra-renal clearance, which mainly represents clearance to the bone-pool, was also significantly higher during production of alkaline (109.2 +/- 20.2 ml/min) than of acid (86.3 +/- 21.3 ml/min) urine. It is suggested, that increased reabsorption of non-ionic hydrogen fluoride (HF) is responsible for the decreased renal clearance during acidic conditions.