Prodrug Of Propofol Research Articles

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats.

We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan injection), a new water-soluble prodrug metabolized to propofol by hydrolysis. Nine adult male Sprague-Dawley rats (398 +/- 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum. A maximum propofol concentration of 7.1 +/- 1.7 microg mL(-1) was reached 3.7 +/- 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 +/- 0.2 and 23.9 +/- 9.9 min), an elimination rate constant of 0.18 +/- 0.01 min(-1) and a central volume of distribution of 0.25 +/- 0.02 L kg(-1). For propofol, the half-life was 1.9 +/- 0.1 and 45 +/- 7 min, the elimination rate constant was 0.15 +/- 0.02 min(-1) and the central volume of distribution was 2.3 +/- 0.6 L kg(-1). The maximum effect on the electroencephalogram (EEG)--EEG suppression for >4 s--occurred 6.5 +/- 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 +/- 7.9 Hz, EC50 = 2.6 +/- 0.8 microg mL(-1), ke0 = 0.35 +/- 0.04 min(-1)). Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

The propofol prodrug GPI 15715* [Aquavan] has achieved its phase-III primary efficacy endpoint

The propofol prodrug GPI 15715* [Aquavan] has achieved its phase-III primary efficacy endpoint

Sedation with GPI 15715, a Water-Soluble Prodrug of Propofol, Using Target-Controlled Infusion in Volunteers: Retracted

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

Population pharmacokinetic model of sedative doses of GPI15715 and propofol liberated from GPI15715

Background GPI15715 (AQUAVAN® Injection, AQ) is a water soluble prodrug of propofol (PR). Pharmacokinetics (PK) of PR liberated from AQ differ from those of PR lipid emulsions. We developed a population PK model of AQ and liberated PR and identified covariates that influenced their PK. Methods In a Phase II colonoscopy sedation study, 5 minutes after fentanyl citrate iv dose (11–201 μg) patients received an AQ iv bolus and up to 4 supplemental iv doses (total dose 495–1675 mg). A total of 597 AQ and 599 PR concentrations from 69 males and 89 females were analyzed using NONMEM. Covariates included age (20–85 yrs, 18 patients≥ 65 yrs), weight (WT 45–140 kg), lean body weight (LBW 37–81 kg), BMI, gender, fentanyl citrate exposure, albumin, creatinine clearance, and lab values. Results Linear 2-comparment models for AQ and PR with a delay compartment between them described the data. CLAQ, V1AQ and CLPR, V1PR increased proportionally with LBW. Model parameters (%SE) under assumption of 100% AQ metabolism to PR were: CLAQ=0.27 L/min (21%), V1AQ=6.4 L (6%), K12AQ=0.023 1/min (56%), K21AQ=0.0032 1/min (52%), KAQ-PR=0.41 1/min (12%), V1PR=1 L (fixed), CLPR=3.7 L/min (18%), K12PR=3.8 1/min (25%), K21PR=0.03 1/min (27%), CLAQLBW=2.5 %/kg (12%), V1AQLBW=1.8 %/kg (21%), CLPRLBW=V1PRLBW=1.6 %/kg (27%). Conclusions Linear population PK model adequately described the data. LBW was a better predictor than WT. Fentanyl citrate did not affect the PK. No clinically significant influence of age was detected. Clinical Pharmacology & Therapeutics (2005) 77, P48–P48; doi: 10.1016/j.clpt.2004.12.076

Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vivo evaluation of cyclic amino acid esters

Cyclic amino acid esters of propofol were synthesized in an attempt to develop new water-soluble anesthetic agents. Their solubility and stability in aqueous solution, and their ability to release propofol in vitro under physiological conditions were determined. L-Proline (6a) and racemic nipecotic acid (6c) esters were found to be highly soluble in water. Sufficiently stable at physiological pH (half-lives >6 h), the alpha-amino acid esters, 6a and 6b, were found to be quantitatively hydrolyzed in plasma and liver esterase solutions within a few minutes, showing prodrug behavior. The in vitro activity of the esters, determined either by the [(35)S]tert-butylbicyclophosphorothionate ([(35)S]TBPS) binding assay or electrophysiological measurements of the action at cloned human receptors, proved to be a mechanism involving allosteric modulation of GABA(A) receptors. Indeed, L-proline (6a), and racemic pipecolinate (6b) and nipecotate (6c), like propofol, reduced [(35)S]TBPS binding, whereas isonipecotate (6d) showed bicuculline-like behavior, increasing [(35)S]TBPS binding. A nonlinear relation between GABA(A) receptor binding affinity and lipophilicity, as assessed by reversed-phase high-performance liquid chromatography, emerged as a trend. The in vivo anticonvulsant and anesthetic activities of prolinate 6a, intraperitoneally administered in water solution, showed that is a water-soluble propofol prodrug candidate for developing formulations useful for parenteral administration.

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats: Retracted

Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats: Retracted

Pharmacodynamics of AQUAVANTM Injection, a Water-Soluble Prodrug of Propofol as a Bolus Injection : A Phase I Dose Escalation Comparison with DIPRIVAN©

Pharmacodynamics of AQUAVANTM Injection, a Water-Soluble Prodrug of Propofol as a Bolus Injection : A Phase I Dose Escalation Comparison with DIPRIVAN©

Target Controlled Infusion (TCI) of AQUAVANTM, a Watersoluble Prodrug of Propofol, for Conscious Sedation in Volunteers

Target Controlled Infusion (TCI) of AQUAVANTM, a Watersoluble Prodrug of Propofol, for Conscious Sedation in Volunteers

Propofol Hemisuccinate Protects Neuronal Cells from Oxidative Injury

Oxidative stress contributes to the neuronal death observed in neurodegenerative disorders and neurotrauma. Some antioxidants for CNS injuries, however, have yet to show mitigating effects in clinical trials, possibly due to the impermeability of antioxidants across the blood-brain barrier (BBB). Propofol (2,6-diisopropylphenol), the active ingredient of a commonly used anesthetic, acts as an antioxidant, but it is insoluble in water. Therefore, we synthesized its water-soluble prodrug, propofol hemisuccinate sodium salt (PHS), and tested for its protective efficacy in neuronal death caused by non-receptor-mediated, oxidative glutamate toxicity. Glutamate induces apoptotic death in rat cortical neurons and the mouse hippocampal cell line HT-22 by blocking cystine uptake and causing the depletion of intracellular glutathione, resulting in the accumulation of reactive oxygen species (ROS). PHS has minimal toxicity and protects both cortical neurons and HT-22 cells from glutamate. The mechanism of protection is attributable to the antioxidative property of PHS because PHS decreases the ROS accumulation caused by glutamate. Furthermore, PHS protects HT-22 cells from oxidative injury induced by homocysteic acid, buthionine sulfoximine, and hydrogen peroxide. For comparison, we also tested alpha-tocopherol succinate (TS) and methylprednisolone succinate (MPS) in the glutamate assay. Although TS is protective against glutamate at lower concentrations than PHS, TS is toxic to HT-22 cells. In contrast, MPS is nontoxic but also nonprotective against glutamate. Taken together, PHS, a water-soluble prodrug of propofol, is a candidate drug to treat CNS injuries owing to its antioxidative properties, low toxicity, and permeability across the BBB.

8 Advances in Clinical Fibrinolysis

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm2 h) from 8.52 ± 0.82 μg/(cm2 h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12μg/(cm2 h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration—time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.