Amphiphilic silicones to reduce the absorption of small hydrophobic molecules.

Silicones (i.e. crosslinked poly(dimethylsiloxane), PDMS) are commonly used material for microfluidic device fabrication. Nonetheless, due to the uncontrollable absorption of small hydrophobic molecules (<1 kDa) into the bulk, its applicability to cell-based drug assays and sensing applications has been limited. Here, we demonstrate the use of substrates made of silicones bulk modified with a poly(ethylene oxide) silane amphiphile (PEO-SA) to reduce hydrophobic small molecule sequestration for cell-based assays. Modified silicone substrates were generated with concentrations of 2 wt.%, 9 wt.% and, 14 wt.% PEO-SA. Incorporation of PEO-SA into the silicone bulk was assessed by FTIR analysis in addition to water contact angle analysis to evaluate surface hydrophobicity. Cell toxicity, absorption of small hydrophobic drugs, and cell response to hydrophobic molecules were also evaluated. Results showed that the incorporation of the PEO-SA into the silicone led to a reduction in water contact angle from 114° to as low as 16° that was stable for at least three months. The modified silicones showed viability values above 85% for NIH-3T3, MCF7, MDA-MB-468, and MDA-MB-231 cell lines. A drug response assay using tamoxifen and the MCF7 cell line showed full recovery of cell toxicity response when exposed to PDMS modified with 9 wt.% or 14 wt.% PEO-SA compared to tissue culture plastic. Therefore, our study supports the use of PEO-SA at concentrations of 9 wt.% or higher for enhanced surface wettability and reduced absorption of small hydrophobic molecules in PDMS-based platforms.

Pharmacokinetic Aspects of Nanoparticle-in-Matrix Drug Delivery Systems for Oral/Buccal Delivery.

Oral route maintains its predominance among the ones used for drug delivery, especially when medicines are self-administered. If the dosage form is solid, therapy gains in dose precision and drug stability. Yet, some active pharmaceutical substances do not present the required solubility, permeability, or release profile for incorporation into traditional matrices. The combination of nanostructured drugs (nanoparticle [NP]) with these matrices is a new and little-explored alternative, which could bring several benefits. Therefore, this review focused on combined delivery systems based on nanostructures to administer drugs by the oral cavity, intended for buccal, sublingual, gastric, or intestinal absorption. We analyzed published NP-in-matrix systems and compared main formulation characteristics, pharmacokinetics, release profiles, and physicochemical stability improvements. The reported formulations are mainly semisolid or solid polymers, with polymeric or lipid NPs and one active pharmaceutical ingredient. Regarding drug specifics, most of them are poorly permeable or greatly metabolized. The few studies with pharmacokinetics showed increased drug bioavailability and, sometimes, a controlled release rate. From our knowledge, the gathered data make up the first focused review of these trendy systems, which we believe will help to gain scientific deepness and future advancements in the field.

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients.

BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: Tacrolimus 24-hour AUC (AUC0-24), peak and trough concentrations (Cmax and Cmin), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC0-24 or Cmin between CYP3A5 expressers and nonexpressers during administration of either IR-Tac or LCPT. With IR-Tac, tacrolimus Cmax was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922.