Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration.

XR9576 is a novel inhibitor of P-glycoprotein (P-gp) that has been shown to reverse P-gp-dependent multidrug-resistance in tumor cell lines and tumor-bearing animals. Here we report the first i.v.

The relationship between paroxetine and the sparteine oxidation polymorphism.

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single-dose (30 mg) and steady-state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration-time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol.hr/L), whereas at steady state the median AUCss tau interphenotype difference was only twofold (4410 versus 2550 nmol.

A review of the metabolism and pharmacokinetics of paroxetine in man.

Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeutically relevant concentrations is about 95%.

Safety of ticarcillin disodium/potassium clavulanate.

Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously. No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man.

Pseudomonic acid, a new antibiotic for topical therapy.

Pseudomonic acid, a new wide-spectrum antimicrobial agent, was evaluated as a 2% formulation in a cream. Animal studies showed that this formulation was just capable of penetrating the skin. When administered parenterally to animals, pseudomonic acid was converted to inactive metabolites that were quickly eliminated from the body.

Human pharmacokinetics of temocillin (BRL 17421) side chain epimers.

The pharmacokinetics of the side-chain epimers of temocillin were investigated in four healthy male subjects following a single iv dose of temocillin disodium (1 g pure free acid) containing 64.2% R-epimer. Plasma and urinary concentrations of the epimers were determined by hplc methods.

Human pharmacokinetics and antimicrobial activities of the temocillin epimers.

The pharmacokinetics of the epimers of temocillin were investigated in 4 healthy male subjects following intravenous administration of 1g of temocillin disodium (free acid) which contains a R : S epimer ratio of approximately 65 : 35. The R epimer had a 2-fold greater total plasma clearance, a 23% larger volume of distribution and a shorter beta half-life than the S epimer. Intermediate values were obtained for total temocillin (R + S) from high pressure liquid chromatography (HPLC) data.

Effect of renal function and dialysis on temocillin pharmacokinetics.

Temocillin pharmacokinetics in renal impairment were investigated following an intravenous bolus injection of 15 mg/kg. The 28 patients were divided into 5 groups of varying renal function, from normal to uraemic [including a group being treated with haemodialysis and a group on continuous ambulatory peritoneal dialysis (CAPD)]. The distribution of temocillin into the tissues was not affected by renal dysfunction.

Temocillin. Summary of safety studies.

Temocillin is a novel injectable beta-lactam antibiotic designed for parenteral use. It is active against the majority of Gram-negative bacteria and is stable to a wide range of beta-lactamases. Disposition and metabolic studies on temocillin in animals and man demonstrate that the drug is well distributed throughout the body tissues and will cross the placenta.

The pharmacokinetics of temocillin in patients with normal and impaired renal function.

The pharmacokinetics of temocillin was studied in 16 subjects with varying degrees of renal functional impairment. The subjects were divided into three groups, depending on their creatinine clearance: Group A greater than 70 ml/min/1.73 m2; Group B 20-70ml/min/1.

Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase.

Sodium pseudomonate was shown to be a powerful competitive inhibitor of Escherichia coli B isoleucyl-tRNA synthetase (Ile-tRNA synthetase). The antibiotic competitively inhibits (Ki 6 nM; cf. Km 6.

Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid.

The mode of action of the antibiotic pseudomonic acid has been studied in Escherichia coli. Pseudomonic acid strongly inhibits protein and RNA synthesis in vivo. The antibiotic had no effect on highly purified DNA-dependent RNA polymerase and showed only a weak inhibitory effect on a poly(U)-directed polyphenylalanine-forming ribosomal preparation.

On the mode of action of pseudomonic acid: inhibition of protein synthesis in Staphylococcus aureus.

The effect of the antibiotic, pseudomonic acid, on the major metabolic processes in Staphylococcus aureus was studied. The primary effect of low concentrations of the antibiotic, leading to bacteriostasis, is inhibition of protein synthesis. Pseudomonic acid also severely inhibits RNA synthesis which can be prevented by chloramphenicol treatment.

Streptozotocin: its excretion and metabolism in the rat.

The excretion of radioisotope following the administration of three specifically 14C-labelled forms of streptozotocin was investigated in the rat using ureter and bile duct cannulation techniques. The urine collected during the first hour following the administration of the drug contained the highest proportion of injected radioactivity (approximately 34% with (3'-methyl-14C)-streptozotocin and approximately 40% each with (1-14C)-and (2'-14C)-streptozotocin. Over the entire experimental period (6 hours), approximately 70% of the injected radioactivity of (1-14C)- and (2'-14C)-streptozotocin appeared in the urine.

Autoradiographic study of the distribution and cellular uptake of (14C) - streptozotocin in the rat.

The distribution and cellular accumulation, in the rat, of three specifically 14C-labelled forms of streptozotocin were investigated. A significant pancreatic accumulation of radioactivity was observed with (3' -methyl-14C)-streptozotocin only. Autoradiographic studies revealed high levels of bound radioactivity in the islet tissue following the administration of (3 -methyl-14C)-streptozotocin whereas much lower levels of radioactivity were detected in the pancreatic tissue following the administration of either (1-14C)-streptozotocin or (2' -14C)-streptozotocin.