In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans.

(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of [(14)C]dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.

In vitro evaluation of concurrent use of commercially available insect repellent and sunscreen preparations.

BACKGROUND: Insect repellents and sunscreens are over-the-counter products extensively used by the general public. Concurrent application of these products has become widespread in many regions across North America, because of concerns about West Nile virus and skin cancers. OBJECTIVES: We investigated whether formulation type, application amount, and sequence would affect the percutaneous absorption profiles of the active repellent and sunscreen ingredients. METHODS: In vitro percutaneous permeation of the repellent N,N-diethyl-m-toluamide (DEET) and the sunscreen oxybenzone from concurrent application of five commercially available products (A, repellent spray; B, repellent lotion; C, sunscreen lotion; D and E, combined repellent/sunscreen lotions) was measured and compared using Franz-style diffusion cells with piglet skin at 37 degrees C. RESULTS: Penetration of DEET in A and B increased by 1640% and 282%, respectively, when C was applied concurrently. Penetration of DEET in D and E was 53% and 79% higher than that in B. Permeation of DEET from A + C (2:1) and A + C (1: 2) increased by 530% and 278%, respectively. Permeation of oxybenzone was 189% and 280% higher in A + C and B + C than in C. Permeation of oxybenzone in D and E was also 221% and 296% higher than that in C. Permeation of oxybenzone was 196% greater when A was applied on top of C than when C was applied on top of A, while oxybenzone in A + C (1:2) permeated 171% more than that in A + C (2:1). CONCLUSIONS: Concurrent application of commercially available repellent and sunscreen products resulted in significant synergistic percutaneous permeation of the repellent DEET and the sunscreen oxybenzone in vitro. The percutaneous penetration profiles were dependent upon the type of formulation, application sequence and application proportion.