The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [ 14 C]dolutegravir at a dose of 20 mg (80 Ci). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t 1/2 ) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

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The application of Chiral Technology, or the (extensive) use of techniques or tools for the determination of absolute stereochemistry and the enantiomeric or chiral separation of racemic small molecule potential lead compounds, has been critical to successfully discovering and developing chiral drugs in the pharmaceutical industry. This has been due to the rapid increase over the past 10-15 years in potential drug candidates containing one or more asymmetric centers. Based on the experiences of one pharmaceutical company, a summary of the establishment of a Chiral Technology toolbox, including the implementation of known tools as well as the design, development, and implementation of new Chiral Technology tools, is provided.

No abstract

The presence of dA tracts in DNA can lead to stable curvature of the DNA, and this curvature can be important in gene regulation, DNA packaging, and other processes. Since damage to DNA may eliminate this stable curvature, the solution state structure of the duplex of d(CGCAAAAATGCG) paired with d(CGCATTDTTCCG), with D indicating an abasic site, has been determined. The undamaged DNA bends into the major groove both in solution and in the crystal state. The presence of the abasic site in the dA tract region induces changes in the DNA structure up to four base pairs away from the damaged site. The structure of the DNA is dependent on whether the abasic site is in the alpha or beta hemiacetal form. These consequences are quite different from the more localized effects that have been observed for "normal" DNAs containing abasic sites. Thus, there appears to be a strong sequence dependence of the structural effects of abasic sites just as there is for undamaged DNA. Furthermore, these results indicate that the presence of an abasic site can alter DNA bending and hence is likely to have significant long range effects on gene regulation and other properties that are dependent on the stable curvature of DNA.