1. GSK2140944 is a novel bacterial topoisomerase inhibitor in development for the treatment of bacterial infections. The metabolism and disposition in healthy human subjects was investigated. 2. Six male subjects received [(14)C] GSK2140944 orally (2000 mg) and as a single 2-hour i.v. infusion (1000 mg). Urinary elimination (59%) was major by the i.v. route, whereas fecal elimination (53%) pre-dominated via the oral route. Accelerator mass spectrometry (AMS) was used for the analysis of plasma and bile samples due to the low level of radioactivity in samples (low specific activity of the doses). Unchanged GSK2140944 was the predominant circulating component (>60% DRM), with the main circulating metabolite M4 formed by oxidation of the triazaacenaphthylene moiety representing 10.8% (considered major) and 8.6% drug-related material by the oral and i.v. route, respectively. Approximately 50% of the oral dose was absorbed and eliminated mainly as unchanged GSK2140944 in urine (∼20% of dose). Elimination via metabolism (∼13% of dose) was relatively minor. The facile oxidation of GSK2140944 to metabolite M4 was believed to be a result of activation by adjacent electron withdrawing groups. 3. This study demonstrates the use of AMS to overcome radioprofiling challenges presented by low specific activity resulted from high doses administration.

1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.

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AIMSThe aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity. METHODSA microtracer study approach, in which a 5 μg radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously. RESULTSThe least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5 h and the geometric mean terminal half-life was 11 days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h −1 and 976 l, respectively, resulting in a terminal elimination half-life of 11 days. CONCLUSIONSTrametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Following oral dosing of 2 mg trametinib, median tmax was 1.5 h and the mean effective half-life (t1/2) was approximately 4 days. Trametinib is greater than 95% protein bound. Trametinib accumulates about six-fold with repeat daily dosing, and the concentration-time profiles showed a flat profile at steady-state with a low peak : trough ratio.• The absolute bioavailability of trametinib has not been previously reported.• The microtracer approach has been used previously to recover i.v. and oral pharmacokinetic parameters, simultaneously, which are used to estimate absolute bioavailability.• Determination of absolute bioavailability improves our understanding of the clinical pharmacology of a compound. WHAT THIS STUDY ADDS• Trametinib has moderate to high bioavailability (72.3%) following oral administration of a 2 mg tablet.• The i.v. microtracer study approach revealed the contribution of high oral bioavailability with low first pass metabolism and a prolonged terminal elimination phase to the pharmacokinetics of trametinib.

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.