Biomedical subjects

R C Hider

Publications and source records attributed to R C Hider.

169 records · Page 10Linked to original sources

PubMedDate not supplied

Metabolism and pharmacokinetics of 1-(2'-hydroxy-ethyl)- and 1-(3'-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-ones in the rat.

The urinary recovery (p.o.) and pharmacokinetics (i.v. and p.o.) of two compounds from the 1-hydroxyalkyl-3-hydroxypyridin-4-one series. 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridine-4-one (CP102) and 1-(3'-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-one (CP106) were studied in the rat. The pharmacokinetics of the 1-carboxyethyl metabolite (CP110) of CP106 was also studied (i.v.). CP102 was not metabolised to any considerable extent with 68.4 +/- 12.2% of the administered dose recovered unchanged in rat urine. In contrast, CP106 undergoes extensive phase I metabolism to form the 1-carboxyalkyl metabolite which accounted for 56.4 +/- 11% of the administered dose with 22.0 +/- 1.0% as unchanged drug. Intravenous and oral pharmacokinetics of CP102 and CP106 were studied in the rat at 450 mumols/kg. The AUCs of CP102 and CP106 after bolus i.v. infusion were 458 +/- 38 and 171 +/- 20 mumols/l.h. The AUC values after bolus oral administration were 318 +/- 46 and 77 +/- 18 mumols/l.h, respectively, with corresponding bioavailabilities (F) of 0.69 and 0.45. The Cmax of CP102 and CP106 were 142 +/- 25 and 70 +/- 15 mumols/l with Tmax values of 0.75 +/- 0.15 and 0.50 +/- 0.10 h, respectively. The CL, MRT and Vdss of CP102 was 1.00 +/- 0.09 l/kg/h, 0.92 +/- 0.04 h and 0.91 +/- 0.05 l/kg, respectively. The corresponding pharmacokinetic parameters for CP106 were 2.64 +/- 0.20 l/kg/h, 0.42 +/- 0.12 h and 1.12 +/- 0.26 l/kg, respectively. Renal clearance (CLR) of CP102 and CP106 were 1.00 +/- 0.18 l/kg and 1.27 +/- 0.31 l/kg respectively. The pharmacokinetics of CP110, which was conducted by the i.v. route only at a dose of 450 mumols/kg, had an AUC of 289 +/- 46 mumols/l.h, CL of 1.56 +/- 0.29 l/kg/h, MRT of 0.25 +/- 0.09 h and Vdss of 0.40 +/- 0.13 l/kg, respectively.

Animals↗

PubMedDate not supplied

The antimalarial effect of iron chelators: studies in animal models and in humans with mild falciparum malaria.

In this study we explore the antimalarial effects of 3-hydroxypyridin-4-ones (CP compounds), a family of bidentate orally effective iron chelators in experimental animal systems in vivo and in vitro, and examine whether the iron chelator deferoxamine (DF) is active against human infection with P. falciparum. There was direct relation between lipid solubility of the CP compounds, which would facilitate membrane transit, and their in vivo antimalarial action, suggesting direct intracellular iron chelation as the most likely explantation for the antimalarial effect of iron chelators. Results of the double-blind, placebo controlled trial of DF in humans with asymptomatic parasitemia provided unequivocal evidence that this iron-chelating agent has antimalarial activity. Depriving the parasite of a metabolically important source of iron may represent a novel approach to antimalarial drug development. DF is a relatively ineffective intraerythrocytic chelator, and our data indicate that other orally effective iron chelators may have superior antimalarial activity in vivo. A systematic screening of available iron chelating drugs may result in the identification of potentially useful antimalarial compounds.

Animals↗

PubMedDate not supplied

In vitro stability of liposomes in the presence of polymers, trehalose and sodium taurocholate.

We report the influence of synthetic polymers, trehalose and sodium taurocholate on the stability of both MLVs* and SPLVs prepared from a range of lipids including synthetic polyhydroxyl lipids. In the absence of cryoprotective agents liposomes were found to release greater than 90 per cent of encapsulated marker when exposed to freeze-thawing or freeze-drying procedures. In the presence of polyvinylpalmitate a marginal enhancement of stability towards freeze-drying was observed, the effect being most marked with cholesterol-containing liposomes. Trehalose was also found to stabilize all preparations investigated towards freeze-drying. In particular SPLVS prepared from (C18:0, C14:0-GMG):EPC:C retained in greater than 90 per cent of the entrapped marker. Addition of polymers to trehalose-containing SPLVS did not further increase the stability. SPLVS prepared from lipids possessing a high transition temperature demonstrated enhanced stability in the presence of bile salts. This effect was most marked with SPLVs prepared from (C18:0, C22:0-GMG):C.

Bile Acids and Salts↗

PubMedDate not supplied

Urinary metabolic profiles in human and rat of 1,2-dimethyl- and 1,2-diethyl-substituted 3-hydroxypyridin-4-ones.

The urinary metabolic profiles of two novel orally active iron chelators, 1,2-dimethyl-3-hydroxypyridin-4-one (CP20 or L1) and 1,2-diethyl-3-hydroxypyridin-4-one (CP94), have been studied in rats. The metabolism of CP20 was also studied in humans. Four novel metabolites of CP20, and a further three metabolites of CP94 were characterized. CP20 was found to undergo extensive phase II metabolism at the 3-hydroxy position, forming predominantly the O-glucuronide, which accounted for 44% of the dose administered in rat and greater than 85% of the dose administered in man. The 3-O-methylated CP20 metabolite (metabolite I) accounted for 1% of the administered dose in both species, whereas the unmetabolized CP20 amounted to 10.5% and 4% of the dose administered in the rats and man, respectively. In contrast, CP94 was extensively hydroxylated at the 2-ethyl position to give its 2-(1-hydroxyethyl) metabolite in the rat, which accounted for 40% of the administered dose. The O-glucuronide metabolite of CP94 accounted for 13.8% of the administered dose, whereas the unmetabolized CP94 amounted to 6.9% of the administered dose. At 72 hr, urinary levels of CP20 and CP94 and their metabolites in the rat accounted for about 55-60% of the administered dose. A large portion of the dose is therefore probably eliminated via the bile. The identity of the above metabolites was established using a combination of two or more of the following techniques: fast atom bombardment-mass spectroscopy, LC-MS, UV-VIS spectroscopy, NMR spectroscopy, specific enzyme hydrolysis assays, and chemical synthesis of compounds.

Animals↗

PubMedDate not supplied

The pharmacokinetics of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in rats.

The pharmacokinetics of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) and its 2-(1-hydroxyethyl) metabolite (metabolite A) were examined in male Wistar rats using a chronically cannulated conscious-rat model. Serial blood samples were assayed by a reversed phase HPLC method with UV detection. Following iv doses of 25, 50, and 100 mg/kg, the parent compound was eliminated from blood in a biexponential fashion with an average systemic clearance of 1.5 liters/hr/kg. The mean terminal elimination half-life was 2.02 hr and the mean volume of distribution at steady state was 2.69 liters/kg. The areas under the curve (AUCs) for the 25, 50, and 100 mg/kg iv doses were 15, 36, and 72 micrograms/ml/hr, respectively, suggesting that the disposition of CP94 in rats obeys linear kinetics. The oral bioavailability of CP94 (100 mg/kg) was about 53%. Peak blood concentration occurred at about 0.5 hr after oral administration. Following iv doses of CP94 at 25, 50, and 100 mg/kg, metabolite A peaked at about 0.75 hr.

Animals↗

PubMedDate not supplied

Pharmacokinetics of representative 3-hydroxypyridin-4-ones in rabbits: CP20 and CP94.

Selected 3-hydroxypyridin-4-ones (HPs) are under clinical investigation as iron chelators. Representative HPs have been shown to be potential aluminum chelators by use of in vitro test systems. This study was conducted to determine systemic availability of representative HPs in rabbits prior to studies of their oral efficacy as aluminum chelators. Each of 12 rabbits was administered 0.45 mmol/kg 1,2-dimethyl- (CP20; L1) and of 1,2-diethyl-3-hydroxypyridin-4-one (CP94; EL1NEt) by gastric lavage and by injection into a lateral ear vein. Each rabbit received both compounds via both routes with at least 7 days between doses. Blood samples (1.5 ml) were collected up to 24 hr after dosing. The HPs were extracted, then analyzed by HPLC with a column packed with graphitized carbon. The mean (+/- SD) systemic clearance, steady-state volume of distribution, mean residence time, mean oral absorption time, and systemic availability for CP20 and CP94 were 0.8 +/- 0.3 and 2.1 +/- 1.4 liter/hr/kg; 1.2 +/- 0.5 and 1.2 +/- 0.5 liter/kg; 1.7 +/- 0.7 and 0.7 +/- 0.3 hr; 0.9 +/- 1.6 and 0.6 +/- 0.5 hr; and 72 +/- 20 and 57 +/- 27%, respectively. Rabbits demonstrated fairly good absorption and rapid elimination of 1,2-dimethyl- and 1,2-diethyl-3-hydroxypyridin-4-one.

Animals↗

PubMedDate not supplied

Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemic patients.

Pharmacokinetic investigation of desferrioxamine (DFO) was conducted in 11 thalassaemic patients following continuous intravenous infusion of 50 mg/kg/24 hr over 48 hr. Serial venous blood samples were obtained at regular time intervals during and on stopping DFO infusion. Plasma samples were processed with the addition of radioactive iron (59Fe) to stabilize free ligand forms of DFO and its metabolites. This resulted in the formation of both radioactive and nonradioactive forms of ferrioxamine and its metabolites. Following solid-phase extraction, plasma samples were analyzed by a reversed-phase HPLC and monitored by simultaneous UV-visible radioactive detection. DFO was found to be eliminated from the blood in a biexponential manner with a systemic clearance of 0.50 +/- 0.24 liters/hr/kg. The terminal half-life was 3.05 +/- 1.30 hr, and the volume of distribution was 1.88 +/- 1.0 liters/kg at the terminal phase and 1.35 +/- 0.65 liters/kg at steady state. The AUC of DFO was 354 +/- 131 mumol/liter.hr. The major metabolite of DFO, DFO-metabolite B, has an initial half-life of 1.33 +/- 0.61 hr and is usually present at lower concentrations relative to the parent compound with an AUC of 191 +/- 106 mumol/liter.hr.

Chromatography, High Pressure Liquid↗