title: In vivo pharmacokinetics and toxicity of a novel hydrophilic oral formulation of the potent non-nucleoside reverse transcriptase inhibitor compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443).
abstract: The thiophene ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI). The pharmacokinetics of 17 different novel oral formulations of HI-443 were compared in an attempt to identify the most suitable dosage form for clinical use in HIV-infected persons. Plasma concentrations of HI-443 were monitored in mice after administration of the drug using these 17 different formulations at three time points. Two-way ANOVA showed highly significant formulation (p < 0.0001), time (p < 0.0001) and formulation*time interaction effects (p = 0.0003). Planned linear contrasts were performed to identify which formulations showed the highest bioavailability at 10, 30, 60 min and at all time points relative to DMSO alone. A significant positive regression was observed comparing bioavailibility of HI-443 at 10 min and hydrophilic-lipophilic balance (HLB) values of the formulations (R2 = 26%, p < 0.0001). The results showed that formulations that were hydrophilic, containing PEG400 and propylene glycol, gave the highest overall drug concentrations over the 60-min time period. The lead oral formulation of HI-443 exhibited a very favorable toxicity profile in BALB/c mice.
authors.affiliation: Paradigm Pharmaceuticals, White Bear Lake, MN 55110, USA. fatih_uckun@tmo.blackberry.net
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
authors.forename: Heather
authors.initials: H
authors.lastname: Tibbles
authors.forename: Douglas
authors.initials: D
authors.lastname: Erbeck
authors.forename: Taracad K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: Sanjive
authors.initials: S
authors.lastname: Qazi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001682:Biological Availability; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D005079:Excipients; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D019946:Propylene Glycol; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity*; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D013056:Spectrophotometry, Ultraviolet; D013890:Thiourea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D005079:Excipients; C403248:HI 443; D014677:Pharmaceutical Vehicles; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D011092:Polyethylene Glycols; D019946:Propylene Glycol; D013890:Thiourea