Contribution of protein binding to the pharmacokinetics of the ghrelin receptor agonist TZP-101 in healthy volunteers and adults with symptomatic gastroparesis: two randomized, double-blind studies and a binding profile study.

BACKGROUND AND OBJECTIVE: TZP-101 is a selective, small molecule ghrelin receptor agonist in clinical development for the treatment of gastric motility disorders. The objectives of this study was to assess pharmacokinetic parameters of TZP-101 after multiple- and single-dose administration to healthy subjects and patients with gastroparesis, respectively, and to determine the contribution of protein binding to its pharmacokinetic behaviour. METHODS: Pharmacokinetics following 30-minute intravenous infusions of single (160-600 microg/kg) doses of TZP-101 in patients with gastroparesis and multiple (80-600 mug/kg/day) doses of TZP-101 in healthy subjects were characterized. TZP-101 protein binding was measured in human, dog, rat, rabbit and monkey plasma using equilibrium dialysis. RESULTS: TZP-101 pharmacokinetic profiles were less than dose proportional in both healthy subjects and patients, most likely because of concentration-dependent protein binding. A small volume of distribution (99-180 mL/kg following single doses) and long half-life (10-20 hours) were concentration independent in both healthy subjects and patients. Systemic clearance increased with increasing dose. Incidence of adverse events was not related to dose or treatment (active vs placebo). TZP-101 binding to human plasma proteins (primarily alpha(1)-acid glycoprotein) was >/=99% between 5 and 15 mumol/L (2.7 and 8.1 microg/mL) and was significantly higher than in other species. CONCLUSIONS: The pharmacokinetic parameters of TZP-101 in patients with gastroparesis and healthy subjects are comparable and display a similar trend toward increased clearance at higher dose levels resulting in little accumulation of TZP-101 at high dose levels and after multiple dosing. Significant protein binding indicates that the fraction of free drug rather than the total plasma concentration should be taken into consideration for human risk assessment based on animal safety data. Furthermore, the concentration of unbound drug should be considered when optimizing the clinical dose.

Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors.

Vernakalant hydrochloride injection (RSD1235) is a relatively atrial-selective antiarrhythmic agent that converts atrial fibrillation rapidly to sinus rhythm. The pharmacokinetics of vernakalant were explored in healthy volunteers and in patients with atrial fibrillation or atrial flutter in 4 clinical studies. Key pharmacokinetic parameters analyzed were the maximum plasma concentration and the area under the plasma concentration-time curve. Vernakalant exhibited linear pharmacokinetics over the dose range of 0.1 mg/kg to 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with atrial fibrillation or atrial flutter who received 1 or 2 vernakalant infusions. Vernakalant was metabolized rapidly via 4-O-demethylation by cytochrome P450 (CYP)2D6 to its major metabolite RSD1385, which then circulated predominantly as an inactive glucuronide conjugate. In most patients, the maximum plasma concentration of RSD1385 glucuronide exceeded that of vernakalant. Unconjugated RSD1385 was found at low levels in all patients demonstrating either a cytochrome P450 CYP2D6 "extensive metabolizer" or "poor metabolizer" phenotype or genotype; however, CYP2D6 poor metabolizers had even lower levels of unconjugated RSD1385. The impact of CYP2D6 metabolizer status on vernakalant exposure was explored in patients with atrial fibrillation or atrial flutter who received a therapeutic regimen (3 mg/kg initially via 10-minute intravenous infusion followed by a second 2 mg/kg 10-minute infusion if atrial fibrillation persisted after a 15-minute observation period). In the subset that received 2 vernakalant infusions, there was little difference in vernakalant maximum plasma concentration or area under the plasma concentration-time curve from the start of the first infusion to 90 minutes between CYP2D6 poor metabolizers and extensive metabolizers or between those who did or did not receive concomitant CYP2D6-inhibitor medications. Gender, age, and renal function did not have a clinically significant influence on the pharmacokinetics of vernakalant. These results suggest that an assessment of CYP2D6 expression may not be needed when vernakalant is administered acutely and intravenously to patients with atrial fibrillation.

Synthesis and biological studies of novel 2-aminoalkylethers as potential antiarrhythmic agents for the conversion of atrial fibrillation.

A series of 2-aminoalkylethers prepared as potential antiarrhythmic agents is described. The present compounds are mixed sodium and potassium ion channel blockers and exhibit antiarrhythmic activity in a rat model of ischemia-induced arrhythmias. Structure-activity studies led to the identification of three compounds 5, 18, and 26, which were selected based on their particular in vivo electrophysiological properties, for studies in two canine atrial fibrillation (AF) models. The three compounds converted AF in both models, but only compound 26 was shown to be orally bioavailable. Resolution of the racemate 26 into its corresponding enantiomers 40 and 41 and subsequent biological testing of these enantiomers led to the selection of (1S,2S)-1-(1-naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane monohydrochloride (41) as a potential atrial selective antiarrhythmic candidate for further development.

Comparison between capillary electrophoresis and high-performance liquid chromatography for the stereoselective analysis of carvedilol in serum.

A high-performance liquid chromatographic (HPLC) assay using a chiral stationary phase was developed and validated for the determination of carvedilol enantiomers in human serum and was compared with a previously developed capillary electrophoresis (CE) method. The CE and the HPLC assay were compared by analyzing a series of serum samples containing racemic carvedilol in different concentrations using the two methods. The concentrations obtained by the two assays were not found to be significantly different indicating that CE and HPLC are comparable in terms of reproducibility and precision for the stereoselective analysis of carvedilol in human serum.

Validation of a capillary electrophoresis assay for assessing the metabolic stability of verapamil in human liver microsomes.

A simple CE assay for the rapid determination of the in vitro metabolic stability of verapamil in human liver microsomes has been developed and validated. Verapamil was used as the prototype drug since it is extensively metabolized in human liver microsomes. The assay showed good intra- (CV < or = 10%) and interday (CV < or = 8%) reproducibility. The recovery of verapamil after incubation at 37 degrees C for 60 min with human liver microsomes was low (15 +/- 1%) and two metabolites were detected. The method is currently in use for assessing the metabolic stability of new drug candidates at an early stage of lead optimization at Cardiome Pharma Corp. (Vancouver, BC, Canada).

Doseamento do flurbiprofeno com hidróxido de sódio / Flurbiprofen assay with sodium hydroxide

Flubiprofeno, antiinflamatório näo-esteróide derivado de ácido fenilalcanóico, eficaz no tratamento de artrite reumatóide e enfermedades relacionadas, foi determinado quantitativamente por volumetria com hidróxido de sódio, usando-se fenolftaleína como indicador

Flurbiprofeno: um novo antiinflamatório näo-esteróide / Flurbiprofen: a new non steroid anti-inflammatory agent

A brief but up-to-date review on flurbiprofen, a non-steroidal antiinflammatory agent recently introduced in therapeutics in Brazil, including antiinflammatory activity, pharmacokinetics, adverse effects, genesis, structure-activity relationships and mechanism of action

Avaliaçäo da eficácia antimicrobiana de soluçöes para lentes de contato / Evaluation of the antimicrobial efficacy of solutions for contact lens

Dez produtos comerciais destinados à limpeza, umidificaçäo e conservaçäo de lentes de contato foram analisados quanto à esterilidade, pH e eficácia de conservantes. Pela inoculaçäo de Pseudomonas aerugiosa ATCC 27853 e contagem periódica dos sobreviventes no decorrer do contato por 7 dias, observou-se que 6 dos 9 produtos estéries atendem à exigência de eficácia antimicrobiana de conservantes, segundo a Farmacopéia Britânica 80