European Journal of Clinical Pharmacology

Taguchi, O.; Hida, W.; Nogami, H.; Inoue, H.; Takishima, T.

doi: 10.1007/BF01046698pmid: 2974417

228 34 34 5 5 O. Taguchi W. Hida H. Nogami H. Inoue T. Takishima First Department of Internal Medicine Tohoku University School of Medicine Seiryo-machi Sendai Japan Summary We studied the effective site of an inhaled aerosol of procaterol, a β 2 -selective adrenergic bronchodilator, in 8 asthmatic patients whose basal lung functions are almost within the normal range in both slow vital capacity (VC) and forced expiratory volume in one second (FEV 1.0 ), and are free from asthmatic attack. In patients who had received procaterol 30 min after inhalation of aerosol, there was no significant change in VC, although FEV 1.0 , maximal expiratory flow at 50% VC , maximal expiratory flow at 25% VC and maximal expiratory flow at 30% VC of partial maximal expiratory flow volume curve improved significantly. On the other hand, in those who had received placebo, none of the parameters changed. Furthermore, Rl decreased and C 0.5 increased significantly during the first 5 min after inhalation of procaterol aerosol. After an interval of 5 min, Rl did not change any further, while C 0.5 continued to improve until 30 min after inhalation of procaterol. These results suggest that procaterol may first dilate the large airway and then may gradually dilate the small airway in bronchial asthma.

Schaaf, L.; Dobbs, B.; Edwards, I.; Perrier, D.

doi: 10.1007/BF01046699pmid: 2974418

228 34 34 5 5 L. J. Schaaf B. R. Dobbs I. R. Edwards D. G. Perrier Department of Pharmacy University of Otago Medical School Dunedin New Zealand Medical Research Council of New Zealand, Toxicology Research Unit University of Otago Medical School Dunedin New Zealand Department of Pharmaceutical Sciences University of Nebraska Medical Center, College of Pharmacy Omaha Nebraska Faculty of Pharmacy University of Toronto Toronto Ontario Canada Summary The disposition kinetics of a new 5-fluorouracil prodrug, 5′-deoxy-5-fluorouridine (5′dFUR, doxifluridine), were investigated in six patients with colorectal carcinoma. Each patient randomly received two single intravenous doses of 5′dFUR (2 and 4 g · m −2 ) on separate days. Plasma concentrations of 5′dFUR fell rapidly with terminal half-lives ranging from 16.1 to 27.7 min. A disproportionate increase in the area under the curve with increasing dose was seen in most patients. Doubling the dose resulted in a 40% decrease in nonrenal clearance (0.60 to 0.37 l · min −1 ) but no apparent change in renal clearance (0.32 to 0.29 l · min −1 ) or steady-state apparent volume of distribution (19.8 to 20.4 l). The mechanism for dose-dependence of 5′dFUR appears to be primarily due to nonlinear elimination associated with nonrenal processes rather than nonlinear plasma protein or tissue binding.

Cheng, Y.; Lundberg, T.; Bondesson, U.; Lindström, L.; Gabrielsson, J.

doi: 10.1007/BF01046700pmid: 3203703

228 34 34 5 5 Y. F. Cheng T. Lundberg U. Bondesson L. Lindström J. Gabrielsson Department of Biopharmaceutics and Pharmacokinetics University of Uppsala Uppsala Sweden Psychiatric Research Center University of Uppsala Uppsala Sweden Hospital Pharmacy Ulleråker Hospital Uppsala Sweden Summary The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.

Legg, B.; Gupta, S.; Rowland, M.; Johnson, R.; Solomon, L.

doi: 10.1007/BF01046701pmid: 3203704

228 34 34 5 5 B. Legg S. K. Gupta M. Rowland R. W. G. Johnson L. R. Solomon Department of Pharmacy University of Manchester Manchester UK Department of Surgery Manchester Royal Infirmary Manchester UK Summary On the basis that unbound concentration better correlates with response than total plasma or blood concentration, the inter- and intra-subject variability in the distribution of cyclosporin within blood and to plasma components was studied in renal transplant patients. Pharmacokinetic aspects were also studied. Blood samples were analysed from patients who received the drug both by a 72-h i.v. infusion and orally (7 mg·kg −1 twice daily). Steady-state was reached within 18 h of starting the i.v. infusion; the plasma data were best fitted by a biexponential equation with half-times of 0.13–1.02 h and 4.3–13.9 h, associated with the two phases. The mean plasma clearance was 700 ml/min. Concentrations during the infusions measured by RIA and HPLC were comparable. Oral profiles showed rapid and extensive absorption. The peak plasma concentrations were 1460–1880 µg·l −1 and occurred 2–4 h after dosing, with bioavailability estimates of 41–113%. Concentrations measured by RIA were higher than by HPLC. Blood-to-plasma concentration ratio measurements of cyclosporin at 37°C decreased with increasing plasma concentration and increased with haematocrit. Fraction unbound, measured by ultracentrifugation, was in the range 0.042–0.122 with an average of 0.068, and varied little in some patients but showed systematic changes with time in others. Cyclosporin binding was found to be related not only to the triglyceride but, more particularly, to the cholesterol-related lipoproteins in plasma. Monitoring cholesterol may be helpful in identifying patients with extremes in binding or with widely varying binding.

Lindholm, A.; Henricsson, S.; Lind, M.; Dahlqvist, R.

doi: 10.1007/BF01046702pmid: 3203705

228 34 34 5 5 A. Lindholm S. Henricsson M. Lind R. Dahlqvist Department of Clinical Pharmacology Huddinge Hospital Huddinge Sweden Department of Transplantation Surgery, Karolinska Institute Huddinge Hospital Huddinge Sweden Summary We have measured total and unbound plasma concentrations of cyclosporin A in seven healthy men after single oral doses (12 mg per kg body weight) on two occasions at least two weeks apart. There was an up to two-fold intraindividual and a more than three-fold interindividual variation in the AUCs of both total and unbound drug. The intraindividual variability in the AUC of cyclosporin is similar to that of many other drugs and needs to be taken into account in the planning of pharmacokinetic studies.

Lepeleire, I.; Hecken, A.; Verbesselt, R.; Kaiser, G.; Barner, A.; Holmes, I.; Schepper, P.

doi: 10.1007/BF01046703pmid: 3203706

228 34 34 5 5 I. De Lepeleire A. Van Hecken R. Verbesselt G. Kaiser A. Barner I. Holmes P. J. De Schepper Department of Pharmacology University of Leuven, Medical School Leuven Belgium Pharmacological Chemistry, Pharma Research and Development Ciba-Geigy Limited Basle Switzerland G. H. Besselaar Associates AG Zollikon Switzerland Summary Single oral doses of 10 mg converting enzyme inhibitor benazepril (CGS 14824A) and 40 mg furosemide were administered to 12 healthy male volunteers either separately or concomitantly. The pharmacokinetic parameters of benazepril were not influenced by coadministration of furosemide. Urinary excretion of total furosemide was significantly reduced by 10 to 20% in the presence of benazepril. This effect was considered clinically insignificant. Erect blood pressure decreased and pulse rate increased only during concomitant treatment.

Bastain, W.; Boyce, M.; Stafford, L.; Morton, P.; Clarke, D.; Marlow, H.

doi: 10.1007/BF01046704pmid: 2904884

228 34 34 5 5 W. Bastain M. J. Boyce L. E. Stafford P. B. Morton D. A. Clarke H. F. Marlow Clinical Pharmacology Unit and Safety of Medicines Department Imperial Chemical Industries PLC, Pharmaceuticals Division Alderley Park Macclesfield Cheshire UK Summary The pharmacokinetics of xamoterol, a β-adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design. After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml·min −1 and the volume of distribution at steady-state (V ss ) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose. Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.

Eichler, H.; Senior, J.; Stadler, A.; Gasic, S.; Pfundner, P.; Gregoriadis, G.

doi: 10.1007/BF01046705pmid: 3203707

228 34 34 5 5 H. G. Eichler J. Senior A. Stadler S. Gasic P. Pfundner G. Gregoriadis Division of Clinical Pharmacology I. Medizinische Universitätsklinik Vienna Austria Medical Research Council Group, Academic Medicine Royal Free Hospital School of Medicine London Britain Institut für Allgemeine Elektrotechnik und Elektronik Technische Universität Vienna Austria Summary The in vivo kinetics and organ uptake of multilamellar liposomes have been studied in healthy volunteers. Sodium fluorescein-containing liposomes composed of equimolar amounts of egg phosphatidylocholine and cholesterol were injected into a peripheral vein in 4 healthy subjects. Blood samples collected from the femoral artery, hepatic vein and pulmonary artery, were analysed for liposomal dye content. The results, showing involvement of the reticuloendothelial system (RES) in the removal of liposomes, confirmed those previously obtained with radiolabelled preparations. Use of an innocuous liposomal marker (sodium fluorescein) and conventional vascular catheterization techniques, as employed here, may provide a reliable and clinically acceptable approach to establishing disease-induced changes in the kinetics of uptake of drug-containing liposomes by the RES, and thus help in the design of protocols for effective treatment.

Ryde, E.; Ahnfelt, N.

doi: 10.1007/BF01046706pmid: 3203708

228 34 34 5 5 E. M. Ryde N. -O. Ahnfelt Department of Human Pharmacology Pharmacia AB Uppsala Sweden Department of Bioanalysis and Kinetics Pharmacia AB Uppsala Sweden Summary Olsalazine sodium (5,5′-azodisalicylic acid (OLZ)) was given to eight healthy volunteers as a 10 mg i.v. bolus dose and as a 1 g oral dose with and without food. To five fasting participants single oral doses of 2 g and 4 g were given. Blood and urine were collected during three weeks after each dose and were assayed for OLZ, a conjugate identified as a sulphate of OLZ (OLZs), 5-aminosalicylic acid (5-ASA), and N-acetyl-5-aminosalicylic acid (ac-5-ASA). The study showed that: 1. OLZ had a very short elimination half-life, mean 56 min. 2. OLZ was absorbed from the intestinal tract to a very small extent, as seen from the low systemic availability and low urinary excretion, 2.3% and 0.31% respectively, for a 1 g dose taken fasting. 3. OLZ was present in the serum partly as a conjugate, which was identified as an O-sulphate. Following the i.v. dose the serum half-life of the O-sulphate was estimated to be 7 days. 4. Food intake did not influence the systemic availability of OLZ and ac-5-ASA. 5. There was no dose-dependent increase of OLZ absorption with single doses up to 2 g, but a 4-g dose showed a more than two-fold increase in the individual peak serum concentration and in the systemic availability of OLZ. However, there was no significant increase in the mean residence time (MRT) for OLZ or in the serum concentration of either 5-ASA or ac-5-ASA at a dose of 4 g.

Hattab, F.

doi: 10.1007/BF01046707pmid: 3203709

228 34 34 5 5 F. N. Hattab Departments of Cariology and Pedodontics, Faculty of Dentistry Jordan University of Science and Technology Irbid Jordan Summary Dried seafoods are a rich source of fluoride (F). The systemic availability of F from seafoods was studied in 3 healthy adults. The plasma concentration and urinary excretion of F for 24 h following the ingestion of 3.87±0.32 mg F (mean ± SD) in seafoods were compared with plasma and urine data following oral administration of 3 mg F in aqueous solution. There was a marked reduction and delay in the absorption of F from seafoods. The relative bioavailability of F from seafoods was 40.8±5.1%. These findings should be taken into consideration when determining the optimum level of daily F intake.