Probing a potential in vivo drug-excipient interaction: temporal effects of a modified β-cyclodextrin on the intravenous pharmacokinetics of a model high-affinity drug ligand.

The investigational synthetic ozonide, OZ209, has previously been shown to have high binding affinity for sulfobutylether(7)-β-cyclodextrin [(SBE)(7)-β-CD] resulting in altered pharmacokinetics when administered intravenously to rats in a (SBE)(7)-β-CD aqueous formulation. In the present study, OZ209 and (SBE)(7)-β-CD have been used to probe whether a modified β-CD excipient, on systemic administration, can bind to and alter the pharmacokinetics of a coadministered drug. When (SBE)(7)-β-CD was administered 60 min after OZ209, a spike in the concentration of OZ209 in blood and plasma was detected within 2 min of the (SBE)(7)-β-CD infusion, and this was accompanied by a temporary decrease in the whole blood-to-plasma partitioning ratio of OZ209, the duration of which was dependent upon the dose of (SBE)(7)-β-CD.

Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice.

Background: The clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs) that do not accumulate in the central nervous system (CNS) to the same extent may have utility. In this study, CNS levels of NGQMs relative to MQ were measured and an early lead chemotype was identified for further optimization.

The first bioreversible prodrug of metformin with improved lipophilicity and enhanced intestinal absorption.

Metformin is a potent antidiabetic agent and currently used as a first-line treatment for patients with type 2 diabetes. Unfortunately, the moderate absorption and uncomfortable gastrointestinal adverse effects associated with metformin therapy impair its use. In this study, two novel prodrugs of a biguanidine functionality containing antidiabetic agent, metformin, were designed, synthesized, and evaluated in vitro and in vivo to accomplish improved lipophilicity and, consequently, enhanced oral absorption of this highly water-soluble drug.

Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol.

A novel ethyl dioxy phosphate prodrug of propofol (3) was synthesized and characterized in vitro and in vivo as safer alternative for phosphonooxymethyl prodrugs. The synthesis of 3 was achieved via vinyl and 1-chloroethyl ether intermediates, followed by addition of phosphate group. Aqueous solubility and chemical stability of 3 was determined in buffer solutions and the bioconversion of 3 to propofol was determined in vitro and in vivo.

Large neutral amino acid transporter enables brain drug delivery via prodrugs.

The blood-brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound.

Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats.

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-month-old) and old (8- to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats.

Plasma and cerebrospinal fluid concentrations of indomethacin in children after intravenous administration.

The objective of this study was to evaluate the cerebrospinal fluid (CSF) permeation of indomethacin in healthy children. The participants (n = 31, aged 4-144 months) received indomethacin (0.35 mg/kg) as a 10-minute intravenous infusion prior to surgery under spinal anaesthesia.

Cerebrospinal fluid distribution of ketoprofen after intravenous administration in young children.

Objective: The purpose of this study was to evaluate the cerebrospinal fluid (CSF) distribution of an NSAID, ketoprofen, in children. Ketoprofen concentrations were determined from the CSF, plasma and protein-free plasma samples.

Methods: Children (n = 21), aged 13-94 months, were given intravenous ketoprofen (1 mg/kg) prior to surgery under spinal anaesthesia.

Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases.

Chronic use of non-steroidal anti-inflammatory drugs may reduce the risk or delay the onset of Alzheimer's disease. To date, only limited information exists on the brain distribution of these drugs. The objective of this study was to determine the absolute brain delivery of ibuprofen by using constant in vivo infusion in rats.