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Background Omaveloxolone is a synthetic oleanane triterpenoid that pharmacologically activates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich's ataxia. Methods The present study evaluated the pharmacokinetics (PK) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich's ataxia patients. Pharmacodynamic (PD) evaluations in monkeys consisted of Nrf2 target gene mRNA expression in peripheral blood mononuclear cells (PBMCs), liver, lung, and brain. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich's ataxia patient PK profile. Results Oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measureable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes in PBMCs and tissues was also observed. Clinically, oral administration of omaveloxolone to Friedreich's ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. Conclusion Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.

The aim of this study was to determine the anti-inflammatory effects of besifloxacin, a novel fluoroquinolone under clinical evaluation for the treatment of ophthalmic infections, in human corneal epithelial cells (HCEpiC).Cytokine expression in primary HCEpiC was stimulated by interleukin-1beta (IL-1beta), and Luminex technology was used to determine the effect of besifloxacin on IL-1beta-induced cytokine release. Effect of besifloxacin on nuclear factor kappa B (NFkappaB), and mitogen-activated protein kinase (MAPK) was assessed by measuring inhibitory kappa B protein (IkappaB) degradation, NFkappaB nuclear translocation, and MAPK phosphorylation by Western blotting. Moxifloxacin, a marketed fluoroquinolone, was used as the control. Anti-inflammatory efficacy of besifloxacin was also evaluated in rabbits infected with methicillin-resistant Staphylococcus aureus (MRSA).Stimulation of HCEpiC with IL-1beta increased release of 12 of the 29 cytokines measured. Besifloxacin significantly inhibited IL-1beta-induced cytokine release in a dose-dependent manner, with a comparable (IL-8) or better (G-CSF, GM-CSF, IL-6, MCP-1, MIP-1beta, TGF-alpha, and TNF-alpha) efficacy compared to moxifloxacin. A significant inhibitory effect of besifloxacin was observed at 1 or 10 microg/ml. Besifloxacin inhibited IkappaB degradation, NFkappaB nuclear translocation, and activation of p38 and JNK MAPKs. Based on improvement of clinical score, besifloxacin showed statistically significant anti-inflammatory effect compared to saline treatment.Besifloxacin acts as an anti-inflammatory agent in corneal epithelial cells in vitro, by inhibiting the NFkappaB and MAPK pathways. Besifloxacin also exhibits anti-inflammatory efficacy in vivo. The anti-inflammatory attribute may enhance its efficacy in the treatment of ocular infections with an inflammatory component and warrants further investigation.

A novel and highly convergent synthesis leading to 2‐phenyl‐quinolines has been developed. As demonstrated in the preparation of 6‐fluoro‐3‐(3‐oxo‐piperazin‐1‐ylmethyl)‐2‐phenyl‐quinoline‐4‐carboxylic acid [(S)‐1‐cyclohexyl‐ethyl]‐amide (8), the method provides fascile access to this class of analogues via the common intermediate 7.

1. Transporters have been increasingly identified as a factor in limiting the oral bioavailability of certain drugs. Previously, the present authors investigated a compound (SB-265123) with an apparent absolute oral bioavailability (Fapp) consistently > 100%, and excluded likely artefactual causes for this observation, as well as standard considerations of non-stationary or non-linear pharmacokinetics. The data led the authors to believe that SB-265123 might be a transporter substrate in the rat, and it was hypothesized that transporter interactions might be responsible for the observed Fapp > 100%. 2. In the present study, a model was proposed incorporating rapid and complete absorption and elimination by a saturable intestinal secretory pathway. Intestinal secretion was demonstrated for SB-265123 using a rat single-pass intestinal perfusion technique. In addition, in a study employing both independent and simultaneous intravenous and oral administration of SB-265123, exposure to SB-265123 was greater than additive on joint intravenous and oral administration, lending further support to the hypothesis of a saturable transporter. Furthermore, in a study with co-administration of GF120918A, a transporter inhibitor, the observed Fapp for SB-265123 was only 84 +/- 17%, providing additional evidence for transporter involvement in the >100% Fapp phenomenon. 3. Experience with SB-265123 illustrates a counterintuitive impact of transporters on oral bioavailability and highlights the importance of considering transporter interactions in the systemic disposition of xenobiotics, even those not demonstrating low oral bioavailability.

1. SB-265123 is a novel alphavbeta3 (the vitronectin receptor) antagonist. Previous rat studies with it revealed an apparent absolute oral bioavailability (Fapp) of greater than 100%. The present studies were conducted to investigate the potential causes for this observation. 2. Of 49 SB-265123 analogues evaluated in rat using an identical experimental design, Fapp100% was observed for 22 of them, suggesting that the observed Fapp100% with SB-265123 was not anomalous. All 22 compounds had clearances15 ml min(-1) kg(-1). However, Fapp100% were not recorded for all low-clearance analogues. 3. Using SB-265123 as a model to investigate potential artefacts, it was demonstrated that using a chiral assay did not decrease Fapp. Additionally, qualitative sample analysis demonstrated that no metabolites were present in the plasma that could interfere with the liquid chromatography coupled with tandem mass spectrometry detection assay. The high Fapp was also dose-order-, delivery system- and vehicle-independent, and was not affected by the feeding status of the animals. Furthermore, a linearity experiment and an absorption study indicated that oral administration of SB-265123 does not result in hepatic portal vein concentrations that exceed the pharmacokinetic linearity of SB-265123. 4. These observations suggest that the observed Fapp100% for SB-265123 is not due to an experimental artefact or an obvious pharmacokinetic non-linearity. The mechanism(s) for this phenomenon is explored further in the second part of the present paper.

1. Inhibition of p38 MAP kinase has been investigated extensively as a potential therapy for cytokine-mediated diseases such as autoimmune and inflammatory diseases. SB-242235 (1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole) is a potent and selective p38 MAP kinase inhibitor; the preclinical pharmacokinetics of SB-242235 have been described previously. The present studies were conducted to describe the in vitro metabolic rates and routes of SB-242235 metabolism, to characterize its in vivo preclinical metabolism, and to use these data to aid in the prediction of the pharmacokinetic behaviour of SB-242235 in man. 2. SB-242235 was metabolically stable in rat, dog, monkey and human hepatic microsomes, isolated hepatocytes and liver slices in vitro. The in vivo preclinical metabolism studies were consistent with the in vitro findings; SB-242235 was minimally metabolized, and was primarily excreted unchanged in the urine (45 and 67% of the administered dose in the rat and monkey, respectively). 3. Allometric scaling using various correction factors predicted that SB-242235 would have low clearance in man with a predicted half-life ranging from 11.5 to 18.7h. This prediction was consistent with the observed mean half-life of 16.4h in the first-in-man study for SB-242235. An allometric scaling method with a correction for interspecies differences in glomerular filtration rate provided the most accurate prediction of the pharmacokinetic behaviour of SB-242235 in humans, although the clinical data also highlight potential difficulties in conducting prospective allometry.

1. SB-242235 (1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole) is a potent and selective p38 MAP kinase inhibitor that may be an effective therapy for cytokine-mediated diseases such as autoimmune or inflammatory diseases. The present studies were conducted to evaluate the pharmacokinetics of SB-242235 in several preclinical species, including rat, dog and monkey. 2. SB-242235 demonstrates generally favourable pharmacokinetic properties in all species examined. Systemic plasma clearance was high in rat, but in the non-rodent species SB-242235 demonstrated low to moderate clearance with plasma half-lives > 4h. Oral bioavailability in each preclinical species was high. In rat and monkey, SB-242235 demonstrated non-linear elimination kinetics that manifested as a decrease in clearance with increasing dose and apparent oral bioavailability > 100% at high oral doses. Furthermore, SB-242235 displayed concentration-dependent plasma protein binding over a concentration range of 1000-10,000 ng ml(-1). 3. In conclusion, SB-242235 demonstrates high oral bioavailability across the major preclinical species, and may thus be a useful tool compound for investigation of the role of p38 inhibition in various disease states. However, the observations of non-linear protein binding and disposition also suggest the need for caution in the design of and data interpretation from such studies.

1. SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)imidazole) is a potent, selective inhibitor of p38 MAP kinase used extensively as a tool inhibitor in various pharmacological and toxicological models. This study was designed to evaluate the pharmacokinetics of SB-203580 in several preclinical species, both to assist with the interpretation of existing studies and to aid in the design of future studies with this inhibitor. 2. In vitro, SB-203580 was stable in mouse, rat, dog, monkey and human plasma over 24 h. However, species differences in plasma protein binding were observed; SB-203580 was 96-97% bound in human plasma and 78-92% bound in other species. These data suggest that protein binding may influence the results of in vitro studies using SB-203580, particularly when comparing results from different in vitro systems that incorporate plasma components. In vivo, SB-203580) demonstrated moderate to high clearance in all species tested, with non-linear elimination observed in the rat at plasma concentrations > 1,000 ngml(-1). Although good solution bioavailability was observed in non-rodents (78% in dog, 32% in monkey), lower and more variable bioavailability was observed in the rat and mouse (3 -48%). 3. These interspecies differences in bioavailability, and the non-linear pharmacokinetics observed in rat, highlight the importance of monitoring SB-203580 systemic exposure in parallel witb the pharmacological endpoint during in vivo pharmacology

Ventilation parameters (minute ventilation, V; tidal volume, Vt; and breathing frequency, f) of female Sprague-Dawley rats were measured during an 8-h exposure to methanol vapor at concentrations of 1000, 5000, 10, 000, 15, 000 and 20, 000 ppm. Rats were exposed individually in a flow-through chamber that permitted simultaneous measurement of ventilation, methanol extraction from the airstream by the animal, and blood methanol concentration. Compared to the whole-body plethysmography with nose-only exposure (WBP) system, the total ventilation of rats in this study was approximately half; the Vt was approximately the same, but f was about 50% lower than reported in WBP exposed rats. The hourly ventilation decreased slightly with increasing blood methanol concentration up to 2000 mg/L; at concentrations exceeding 2000 mg/L, the hourly ventilation decreased more significantly. The exposure system method studied simultaneously yielded information on the extraction of methanol from the airstream, effi...