Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers.

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism in conjunction with warfarin for the prevention of DVT in patients undergoing hip or knee replacement surgery, and as an anticoagulant in hemodialysis circuits. Its average molecular weight ranges between 5500 and 7500 daltons (Da); the percentage of chains with molecular weight lower than 2000 Da is not more than 10% in the marketed tinzaparin formulation. While this fraction is generally considered pharmacologically inactive, this has never been evaluated in vivo. The importance of the < 2000 Da fraction on the anticoagulant pharmacodynamics of tinzaparin assessed by anti-Xa and anti-IIa activity was studied in a two-way crossover trial. In this trial, 30 healthy volunteers received a single 175 IU/kg subcutaneous administration of tinzaparin containing approximately 3.5% of the < 2000 Da fraction and a tinzaparin-like LMWH containing 18.3% of the < 2000 Da fraction. The anti-Xa/anti-IIa ratios of the drug substances were comparable at 1.5 and 1.7 for tinzaparin and the tinzaparin-like LMWH, respectively. Both formulations were safe and well tolerated. Mean maximum plasma anti-Xa activity (A(max)) was approximately 0.818 IU/ml at 4 h following tinzaparin injection. Mean maximum plasma anti-IIa activity was 0.308 IU/ml at 5 h postdose. Intersubject variation was lower (< 18% for both anti-Xa and anti-IIa metrics) than in previous fixed-dose administration studies. There was no correlation between anti-Xa or anti-IIa AUC or A(max) and bodyweight in the present study supporting the weight-adjusted dosing regimen. Individual anti-Xa and anti-IIa profiles following the single 175 IU/kg subcutaneous administration of the tinzaparin-like LMWH were similar to that obtained with tinzaparin. Based on average equivalence criteria, the two LMWH preparations were determined to be bioequivalent using either anti-Xa or anti-IIa activity as biomarkers. The calculated intrasubject variabilities were low (< 14% for anti-Xa activity and < 18% for anti-IIa activity) yielding little evidence for a significant Subject x Formulation interaction. In summary, anti-Xa and anti-IIa activity following a single subcutaneous administration of tinzaparin 175 IU/kg to healthy volunteers yielded activity consistent with targeted therapeutic levels derived from previous trials in adult DVT patients. Weight-based dosing for the treatment of DVT appears rational based on the reduction in anti-Xa and anti-IIa variability consistent with the recommendation derived from earlier fixed-dose pharmacokinetic studies. Furthermore, differences in the percentage of molecules in the < 2000 Da molecular weight fraction of tinzaparin do not translate into differences in anti-Xa and anti-IIa activity in vivo.

Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12-19 mL/min) than that seen in previous studies in patients with cancer (approximately 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.

Bromide pharmacokinetics in cystic fibrosis.

OBJECTIVE: Individuals with cystic fibrosis (CF) have altered kinetics for a number of drugs, most often an increased volume of distribution (Vd) per body weight and increased clearance per body weight. To further evaluate those differences, we studied bromide kinetics (Vd, elimination rate constant, and clearance) and body mass index in eight adults with mild-to-moderate forms of CF, 21 obligate carriers of the CF gene, and 21 healthy controls. Bromide distribution approximates the extracellular fluid volume and bromide is excreted unchanged by the kidney. DESIGN: Individuals were given a single oral dose of bromide (50 mg/kg), and serum bromide concentrations were measured over 4 weeks. Bromide pharmacokinetics (Vd, elimination rate constant, and clearance) were determined using a one-compartment model with first-order kinetics. Body mass index was determined for each individual. RESULTS: Individuals with CF had a significantly greater lean body mass per kilogram as estimated by body mass index compared with individuals in the obligate carrier and control groups. The mean (+/- SD) Vd per kilogram for the CF group (311 +/- 29 mL/kg) was significantly greater than that of the obligate carrier group (261 +/- 26 mL/kg) and the control group (274 +/- 30 mL/kg). However, the mean (+/- SD) Vd per square meter for the three groups was similar. The mean elimination rate constant for the CF group (3.55 +/- 0.98 x 10(-3)/h) was significantly greater compared with the mean elimination rate constant for the obligate carrier group (2.55 +/- 0.36 x 10(-3)/h) and the control group (2.58 +/- 0.49 x 10(-3)/h). The mean (+/- SD) clearance per kilogram was also significantly greater for the CF group (1095 +/- 283 microL/kg per hour) compared with the obligate carrier group (664 +/- 100 microL/kg per hour) and the control group (700 +/- 115 microL/kg per hour). CONCLUSIONS: These findings indicate that individuals with CF have a greater Vd per kilogram for bromide and drugs that distribute in the extracellular fluid volume because of their greater lean body mass per kilogram. The findings also suggest that individuals with CF have a greater renal clearance of bromide and presumably of other anionic drugs excreted by the kidney. The results emphasize the importance of body composition in drug disposition.

Protein binding of vancomycin in a patient with immunoglobulin A myeloma.

Atypical vancomycin pharmacokinetics were observed in an immunoglobulin A myeloma patient. Drug concentrations in serum were extremely elevated, the elimination half-life was prolonged despite normal renal function, and the vancomycin therapy was ineffective. Extensive binding of vancomycin, presumably by high concentrations of an aberrant immunoglobulin A protein, may have accounted for these observations.

Dose and flow dependence of 5-fluorouracil elimination by the isolated perfused rat liver.

The influences of dose and hepatic blood flow on the elimination of 5-fluorouracil (FUra) by the isolated perfused rat liver were investigated. FUra was injected into the perfusion reservoir and then serial blood samples were collected over 2-3 h. FUra concentration was determined chromatographically. In some experiments, the conversion of [2-14C]FUra to 14CO2 was also determined. With livers perfused at 20 ml/min, the initial decrease in plasma FUra concentration was linear with time (apparent zero-order kinetics); at concentrations below about 25 microM, the decrease became exponential (apparent first-order kinetics). Semilogarithmic plots of FUra concentration/dose versus time obtained with different doses were not superposable, consistent with saturable (Michaelis-Menten) elimination. Vmax and Km were 6-11 nmol/ml/min and 33-45 microM, respectively. Hepatic clearance during first-order elimination was close to 20 ml/min. About 84% of the dose was converted to CO2, indicating that catabolic metabolism was the principal route of elimination. As hepatic blood flow increased from 10 to 30 ml/min, Vmax was unchanged but Km decreased progressively from 84 to 32 microM, and clearance increased from 12 to 29 ml/min. It was concluded that hepatic FUra elimination is highly dependent upon both dose and blood flow.

The disposition of 6-deoxyacyclovir, a xanthine oxidase-activated prodrug of acyclovir, in the isolated perfused rat liver.

The antiviral drug, acyclovir, has been used in the treatment of chronic type B hepatitis. High serum concentrations of acyclovir are required to achieve inhibition of hepatitis B viral replication. Because only 15 to 20% of an oral dose is absorbed, it is necessary to administer acyclovir by intravenous infusion. 6-Deoxyacyclovir, an analog of acyclovir, is well absorbed when given orally, and is converted to acyclovir by xanthine oxidase which is present in the gut and liver. This study has examined the hepatic disposition of 6-deoxyacyclovir in a 100 ml recirculating (12 ml per min) perfused rat liver system. Following administration of a bolus dose of 5 mumoles 6-deoxyacyclovir to the reservoir, perfusate concentrations of 6-deoxyacyclovir declined monoexponentially, as the metabolite acyclovir appeared in the perfusate. Addition of the xanthine oxidase inhibitor allopurinol (5 mg) to the perfusate reservoir prior to the administration of 6-deoxyacyclovir resulted in impaired hepatic metabolism of 6-deoxyacyclovir, as demonstrated by a 47% reduction in systemic clearance rate (4.5 +/- 0.4 to 2.4 +/- 0.9 ml per min; p less than 0.05) (mean +/- S.E., n = 6) and a 1.8-fold increase in terminal elimination half-life of 6-deoxyacyclovir (23.5 +/- 2.7 to 42.7 +/- 4.1 min; p less than 0.05), accompanied by a 30% reduction in appearance of acyclovir. The efficient hepatic conversion of 6-deoxyacyclovir to the active antiviral drug, acyclovir, provides a rationale for trials of oral 6-deoxyacyclovir in the treatment of chronic type B hepatitis.

Active uptake of propranolol by isolated rabbit alveolar macrophages and its inhibition by other basic amines.

Propranolol and other basic amines are concentrated by the lung. To test the possibility that the alveolar macrophage might participate in this process, the uptake of dl-[3H]propranolol was studied in macrophages isolated from healthy male rabbits. Uptake was time, temperature, and pH dependent and was reduced in the presence of inhibitors of cellular energy metabolism, such as sodium azide, iodoacetate, sodium cyanide and 2,4-dinitrophenol. It was abolished by sonication of the cell suspension. Scatchard plots suggested at least three uptake processes, one of which appeared to be partition. Uptake of dl-[3H]propranolol was inhibited equally by increasing concentrations of both the dextro- and the levo-isomers, as well as the racemate. It was also markedly inhibited by the lysomotropic agents, ammonium chloride and chloroquine, and by a number of tertiary amines including imipramine, chlorpromazine and methadone. Endogenous amines, including noreprinephrine, epinephrine and histamine had no effect on uptake. These observations suggest that uptake processes in the lung for exogenous basic amines may differ from those for endogenous amines. Although uptake of endogenous amines has been localized to the vascular endothelium, the lysosome may be one intracellular site of accumulation for exogenous amines.

Uptake of propranolol by the lung and its displacement by other drugs: involvement of the alveolar macrophage.

The role of the alveolar macrophage in the uptake of 3H-propranolol by the isolated perfused rabbit lung and displacement of 3H-propranolol from this site has been investigated. Removal of 3H-propranolol (100 microgram) by the lung was characterized by a rapid distribution phase (t1/2 min) and a slower elimination phase with a clearance of 22.4 ml/min (t1/2 = 47 min). Addition of chlorpromazine (1 mg) at 30 min was followed by a twofold increase in perfusate concentrations of 3H-propranolol which was also associated with a reduction of 3H-propranolol in macrophages recovered from lungs at the end of perfusion experiments. Experiments using isolated alveolar macrophages demonstrated uptake of propranolol and marked inhibition by 100-fold higher concentrations of chlorpromazine and imipramine. In the intact dog, injection of imipramine (1 mg/kg) 60-70 min after bolus injection of 3H-propranolol (0.3 mg/kg) was associated with an immediate increase in blood levels of 3H-propranolol consistent with tissue redistribution. It is concluded that chlorpromazine and imipramine can displace propranolol from the lung,and that the alveolar macrophage is involved in this process.