Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC 50 values > 30 mM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC 50 = 1.9 mM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.

Drug transporters can have a significant impact on the absorption, distribution, metabolism, excretion, and toxicity of a drug (Borst and Oude Elferink, 2002). Transporters can be effective barriers to drug exposure, be the rate determining step in the uptake and/or excretion of a compound or metabolite, and be a cause of drug-drug interactions. Drug efflux transport systems are the most extensively studied family of drug transporters owing to the phenomenon of multidrug resistance, in which cancer cells become cross-resistant to multiple cytotoxic anticancer agents after treatment with only a single drug (Borst and Oude Elferink, 2002;Lepper et al., 2005). Drugs that are substrates for efflux transporters are pumped out of the cell to result in decreased intracellular accumulation, permitting cancer cells to survive lethal doses of cytotoxic drugs. This phenomenon has been characterized in a number of cancers including breast cancer.Breast cancer is the most prevalent cancer in the world, affecting more than 4 million women (Parkin et al., 2005). Each year, breast cancer is diagnosed in more than 1 million women, and 450,000 die of this disease. Breast cancer is frequently associated with increased expression and activation of the epidermal growth factor receptor (EGFR; also known as ErbB), a family of transmembrane tyrosine kinase receptors (Rowinsky, 2004;. These Article, publication date, and citation information can be found at

Hypertrophic scarring (HTS) is an aberrant form of wound healing that is associated with excessive deposition of extracellular matrix and connective tissue at the site of injury. In this review article, we provide an overview of normal (acute) wound healing phases (hemostasis, inflammation, proliferation, and remodeling). We next discuss the dysregulated and/or impaired mechanisms in wound healing phases that are associated with HTS development. We next discuss the animal models of HTS and their limitations, and review the current and emerging treatments of HTS.

Aim: We assessed the utilization of the National Institutes of Health Quality of Life in Neurological Disorders (Neuro-QoL) in pediatric patients with Sturge-Weber syndrome, a rare neurovascular disorder which frequently results in seizures, brain atrophy, calcification, and a range of neurological impairments. Methods: Subjects were seen clinically and consented for research. All 22 patients filled out the Pediatric Neuro-QoL. The Neuro-QoL subscores were converted to T-scores to compare with the referenced control population. Twenty-one participants also filled out the Brain Vascular Malformation Consortium Database Questionnaire containing data pertaining to Sturge-Weber syndromeerelated medical history, medications, comorbidities, and family history. All data were analyzed with a significance threshold of P < 0.05. Results: Cognitive function quality of life was significantly lower (P < 0.001) in pediatric patients with Sturge-Weber syndrome compared with referenced control subjects. Male gender (P = 0.02) was associated with lower cognitive function Neuro-QoL.

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