Understanding the Mechanism and Extent of Transplacental Transfer of (-)-∆ -Tetrahydrocannabinol (THC) in the Perfused Human Placenta to Predict In Vivo Fetal THC Exposure.

Cannabis use during pregnancy may cause fetal toxicity driven by in utero exposure to (-)-∆ -tetrahydrocannabinol (THC) and its psychoactive metabolite, (±)-11-hydroxy-∆ -THC (11-OH-THC). THC concentrations in the human term fetal plasma appear to be lower than the corresponding maternal concentrations. Therefore, we investigated whether THC and its metabolites are effluxed by placental transporters using the dual cotyledon, dual perfusion, term human placenta.

Predicting Human Fetal Drug Exposure Through Maternal-Fetal PBPK Modeling and In Vitro or Ex Vivo Studies.

Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal-fetal physiologically based pharmacokinetic (PBPK) modeling and simulation.

The next frontier in ADME science: Predicting transporter-based drug disposition, tissue concentrations and drug-drug interactions in humans.

Predicting transporter-based drug clearance (CL) and tissue concentrations (TC) in humans is important to reduce the risk of failure during drug development. In addition, when transporters are present at the tissue:blood interface (e.g.

Characterizing and Quantifying Extrahepatic Metabolism of (-)-Δ-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, (±)-11-Hydroxy-Δ-THC (11-OH-THC).

(-)-Δ-Tetrahydrocannabinol (THC) is the psychoactive constituent of cannabis, a drug recreationally consumed orally or by inhalation. Physiologically based pharmacokinetic (PBPK) modeling can be used to predict systemic and tissue exposure to THC and its psychoactive metabolite, (±)-11-hydroxy-Δ-THC (11-OH-THC). To populate a THC/11-OH-THC PBPK model, we previously characterized the depletion clearance of THC (by CYP2C9) and 11-OH-THC (by UDP-glucuronosyltransferase (UGT), CYP3A, and CYP2C9) in adult human liver microsomes.

In Vivo-to-In Vitro Extrapolation of Transporter-Mediated Renal Clearance: Relative Expression Factor Versus Relative Activity Factor Approach.

About 30% of approved drugs are cleared predominantly by renal clearance (CL). Of these, many are secreted by transporters. For these drugs, in vitro-to-in vivo extrapolation of transporter-mediated renal secretory clearance (CL) is important to prospectively predict their renal clearance and to assess the impact of drug-drug interactions and pharmacogenetics on their pharmacokinetics.

Abundance of P-Glycoprotein and Other Drug Transporters at the Human Blood-Brain Barrier in Alzheimer's Disease: A Quantitative Targeted Proteomic Study.

The human blood-brain barrier (BBB) transporter P-gp can efflux amyloid-β (Aβ) out of the central nervous system (CNS). Aβ is thought to be the causative agent for Alzheimer's disease (AD). Using positron emission tomography imaging, we have shown that BBB P-gp activity is reduced in AD, as quantified by the in vivo brain distribution of the P-gp probe [ C]-verapamil.

Neuromyelitis optica practice and prescribing changes in the setting of Covid19: A survey of neurologists.

Purpose: This study reports and analyzes the findings from the responses of 192 neurologists in the United States and Canada to a new survey instrument distributed in April 2020 to assess NMO practice and prescribing changes during the Covid19 pandemic.

Principal Results: 92% of responding neurologists considered their NMO patients to be at an elevated risk of acquiring Covid19. They also indicated sharp declines in visits, delays in treatment and related services, and several unmet needs deterring treatment.

Impact of COVID-19 on U.S. and Canadian neurologists' therapeutic approach to multiple sclerosis: a survey of knowledge, attitudes, and practices.

Objective: To report the understanding and decision-making of neuroimmunologists and their treatment of patients with multiple sclerosis (MS) during the early stages of the SARS-CoV-2 (COVID-19) outbreak.

Methods: A survey instrument was designed and distributed online to neurologists in April 2020.

Results: There were 250 respondents (response rate 21.

Pharmacokinetics of dacarbazine (DTIC) in pregnancy.

Purpose: The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1).

Methods: Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin's lymphoma. Drug concentrations were measured by HPLC.