Development of Jaspine B analysis using LC-MS/MS and its application: Dose-independent pharmacokinetics of Jaspine B in rats

1. The pharmacokinetics of intravenous and oral atenolol (50 mg) in six healthy volunteers was studied. Plasma, saliva and urine were collected up to 24 h after each dose. 2. There was no significant difference in atenolol half-life when administered by the two routes. Bioavailability of the orally administered atenolol was 50%. 3. Atenolol levels in saliva required about 2 h to reach equilibrium with plasma drug levels. 4. A comparison between the pharmacokinetics and pharmacology of atenolol was made in twelve healthy subjects. 5. Dose-independent pharmacokinetics were observed. Reductions in resting heart rate and arterial blood pressure were proportional to either the logarithm of dose or area under the plasma concentration time curve or cumulative urinary atenolol excretion. 6. Plasma elimination half-life in five subjects with renal failure was prolonged.

Effect of dose on the biodistribution and pharmacokinetics of PLGA and PLGA–mPEG nanoparticles

To study the pharmacokinetics and pharmacodynamics of the novel topoisomerase I inhibitor and antitumor agent 9-amino-20(S)-camptothecin in patients with solid tumors after repeated oral administration. Thirty-two patients with cancer received oral 9-aminocamptothecin formulated in capsules with polyethylene glycol-1000 as excipient at doses that ranged from 0.25 to 1.5 mg/m2/day. Serial plasma and saliva samples were obtained on days 1 and 6 or days 1 and 8 of the first cycle and analyzed for the lactone and carboxylate forms of 9-aminocamptothecin by HPLC. 9-Aminocamptothecin showed linear and dose-independent pharmacokinetics, with extremely small intrapatient kinetic variability (coefficient of variation: <10%). However, interpatient variability in plasma pharmacokinetics was large (coefficient of variation: 99%). The relative extent of lactone to carboxylate interconversion was large (>90%) and predictable from individual pretreatment serum albumin values (P = .0099). The 9-aminocamptothecin concentration ratio in plasma and saliva was strongly patient dependent, and highly variable around a mean value of <0.8, suggesting that saliva is an unreliable matrix for kinetic monitoring. The area under the curve of the lactone form of 9-aminocamptothecin was significantly correlated with the dose-limiting hematologic toxicity (P < .001). Our data indicate that the large interindividual pharmacodynamic variability in response to 9-aminocamptothecin is caused mainly by a variability in kinetic characteristics, suggesting that a kinetic-dynamic guided study design is warranted in future clinical investigations.

N8 is a new recombinant factor VIII (rFVIII) compound produced and formulated without human- or animal-derived protein. The aims of the present studies were to evaluate the pharmacokinetics and pharmacodynamics properties of N8 and to compare with a commercially available rFVIII product (Advate(®)) in haemophilia A mice. The pharmacokinetics were evaluated after single i.v. administration of 80, 120 and 280 IU kg(-1) of N8 and Advate(®) and measurements of FVIII blood concentrations as a function of time. The efficacy and dose response curves of N8 and Advate(®) (1-200 IU kg(-1)) were evaluated in a tail bleeding model. Furthermore, the effects in a newly developed haemophilia knee joint haemarthrosis model were investigated. No significant differences were found in the pharmacokinetic parameters between N8 and Advate(®). The clearances were 11 ± 1 vs. 10 ± 2 mL h(-1) kg(-1) (P = 0.14) and the half-lives 7.2 ± 0.9 vs. 7.7 ± 1.4 h (P = 0.31) after administration of N8 and Advate(®) respectively. Dose-independent pharmacokinetics was shown, and comparable efficacy and potency were shown between N8 and Advate(®) in the tail bleeding model. Both compounds normalized the bleeding at the dose of 200 IU kg(-1), and for blood loss ED(50) values of 27 IU kg(-1) (N8) and 28 IU/kg (Advate(®)) were found (P = 0.97). In the haemarthrosis model, treatment with N8 and Advate(®) at 200 IU kg(-1) reduced the mean increase in the joint diameter significantly from 1.23 ± 0.19 to 0.32 ± 0.08 mm (P < 0.01) and 0.25 ± 0.08 mm (P < 0.001) respectively. Pharmacokinetics and pharmacodynamics of N8 and Advate(®) were comparable after i.v. administration to haemophilia A mice.

Dose-Independent Pharmacokinetics of a New Reversible Proton Pump Inhibitor, KR-60436, after Intravenous and Oral Administration to Rats: Gastrointestinal First-Pass Effect

The third generation quinolones, ciprofloxacin, enoxacin, fleroxacin, norfloxacin, ofloxacin and pefloxacin are all quickly and quantitatively well (75-95% of an oral dose) absorbed upon oral administration. The maximum serum concentrations appear after 1-2 hours. The serum and urine concentrations after oral or intravenous ciprofloxacin are directly proportional with the doses and follow normal, dose-independent pharmacokinetics. Ciprofloxacin and norfloxacin reach the same serum levels after the same doses. Steady-state levels are indifferent from those after the first dose. In contrast, enoxacin, oflaxacin and pefloxacin do reach somewhat higher levels after chronic administration. Ciprofloxacin is eliminated by the kidneys (active tubular secretion which is blocked by probenecid) (60% after an intravenous administration), by metabolism and by the transintestinal route. Metabolism is minimal (ca. 15-20% for ciprofloxacin and norfloxacin). Transintestinal elimination implies that the drug is eliminated by transport across the intestinal wall without significant biliary elimination (which is less than 1%). Penetration into tissues occurs readily. Concentrations in prostate secretion are high for ciprofloxacin and norfloxacin. Ciprofloxacin reaches high intracellular concentrations; within human neutrophils the levels reach 6 times the concentrations in the surrounding fluid. Concentrations in bile and tissues are in general comparable to those in serum. Cerebrospinal fluid (CSF) concentrations are low when meningi are normal, but 40-90% of the serum levels when the meninges are inflamed. Because the transintestinal route of elimination compensates for loss of renal elimination, the serum half-life of ciprofloxacvin is raised only to 5-10 hours even in total renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-independent pharmacokinetics of a candidate for diabetic neuropathy, SR-4668, after intravenous and oral administration to rats: Intestinal first-pass effect

A total of 13 patients with ovarian cancer were studied during the initial two courses of i.v. thio-TEPA treatment they underwent after primary surgery. Following an increase in the dose from 60 to 80 mg for the second course, no sign of saturation of thio-TEPA elimination processes or of formation of the metabolite TEPA occurred, indicating dose-independent pharmacokinetics. Myelosuppression after courses was registered by serial measurements of platelets and leukocytes. The time to platelet nadir was quite uniformly 3 weeks and tended to be longer than that of leukocytes, which averaged 2 weeks but showed greater interindividual variation. Linear regression analyses of pharmacokinetic parameters versus myelosuppression revealed statistically significant correlations between thio-TEPA pharmacokinetics and the percentage of reductions in leukocytes and platelets at their mean nadirs. In contrast, no such correlation could be demonstrated for TEPA despite its greater exposure to the body in terms of AUC. We advocate further investigation of this pharmacokinetic-pharmacodynamic relationship so as to establish individualized dosing of thio-TEPA.

Pharmacokinetics of acyclovir in humans following intravenous administration: A model for the development of parenteral antivirals

The use of glycolipids and hydrophilic polymers in avoiding rapid uptake of liposomes by the mononuclear phagocyte system

The aim of this study was to investigate the pharmacokinetics of (-)-epicatechin (EC) in rabbits after intravenous, intraperitoneal, and oral administration. A two-compartment model was used to describe the pharmacokinetics of EC after intravenous administration. EC showed dose-independent pharmacokinetics after intravenous administration. In addition, the area under the concentration-time curve was proportional to the dose over the range 5-25 mg/kg. After intraperitoneal administration of 25 mg/kg, a high percentage of EC escaped from first-pass hepatic elimination. After oral administration of 50 mg/kg, there was a great variation in the pharmacokinetics, and the mean oral bioavailability of EC was 4%. There was no significant difference in the elimination rate constants in all treatments (p>0.05). In conclusion, after intravenous, intraperitoneal, and oral administration of EC, the EC exhibits dose-independent pharmacokinetics in rabbits. The first-pass effect did not participate in the low oral bioavailability. Base on the results of the present study, the other factors may contribute the low oral bioavailability.

Dose- and time-dependent pharmacokinetics and plasma protein binding of pindolol were studied in patients with idiopathic cardiomyopathy who had mild to moderate congestive heart failure. The binding and plasma concentrations of pindolol at various times following the oral administration of single 5- and 10-mg doses and multiple 10-mg doses were determined. The binding of pindolol to plasma protein was time-dependent, increasing from 26% on the first day to 31% during the third day of treatment (P less than .05); this was probably due to increased alpha-1-acid glycoprotein concentration. Analysis of the plasma concentration-time data indicated dose-independent pharmacokinetics. Pindolol pharmacokinetics were time-dependent in one patient. Absorption and elimination half-lives ranged between 0.05 to 0.6 and 1.6 to 7.2 hours, respectively.

Overview of acyclovir pharmacokinetic disposition in adults and children

The pharmacokinetic behavior of navelbine was investigated in 19 patients presenting with advanced cancers (mainly women with breast cancer). Navelbine was given orally at seven dose levels of up to 200 mg/week. For a given dose, patients received four successive weekly treatments. Five subjects also received two different doses. After drug administration, plasma was collected for 48 or 72 h and monitored for navelbine concentration by radioimmunoassay. Absorption of navelbine was very rapid after oral administration: maximal drug concentrations were reached within the first 1 or 2 h (Tmax, 0.9-1.75 h; cmax, 70.9-832.6 ng/ml), with absorption constants ranging from 0.85 to 2.42 l/h. A comparison of dose-normalised plasma concentration profiles revealed significant time dependence in six evaluable patients (P less than 0.001). Only four subjects who received low doses (less than or equal to 100 mg/week) exhibited time-independent kinetics. All of the five patients who were treated at different doses displayed apparent dose dependence (P less than 0.001). No individual profile was characterised by both time- and dose-independent pharmacokinetics. In all, 18 patients presented biphasic plasma concentration-decay patterns, and only 1 subject exhibited monophasic decay kinetics. The navelbine pharmacokinetic parameters obtained following oral administration were similar to those observed after i.v. bolus injection and were characterised by high oral clearance (0.43-1.45 1 h-1 kg-1), a large apparent volume of distribution (27.4-45.9 1/kg), and a long terminal half-life (24.2-56.5 h). Large intra- and inter-individual variations in pharmacokinetic parameters were observed. Moreover, after a high dose of 200 mg, an enterohepatic cycle and/or a delay in navelbine's absorption at a distal intestinal site as evidenced by a marked plasma level rebound was observed.

Long-circulating or StealthR liposomes (S-liposomes) have a number of important properties which make them good candidates for targeting applications. These include long circulation half-lives, dose-independent pharmacokinetics and ability to move through the lymph after subcutaneous injection. A number of techniques are available for attaching antibodies to the surface of S-liposomes. S-liposomes retain their prolonged circulation times in the presence of bound antibody. In the case of liposomes containing polyethylene glycol-lipid derivatives, the ability of bound antibody to recognize its target is dependent on the molecular weight of polyethylene glycol contained in the liposomes. Antibody-mediated specific binding of S-liposomes to cells in culture could be demonstrated, as well as increased cytotoxicity in vitro of targeted S-liposomes containing anticancer drugs. Targeting of antibody-containing S-liposomes could also be demonstrated in vivo. In one therapeutic application, dramatic increases in survival rate could be demonstrated in mice bearing lung squamous cell carcinoma following treatment with doxorubicin entrapped in S-liposomes with attached monoclonal antibody.