Dysregulation of Human Hepatic Drug Transporters by Proinflammatory Cytokines.

Proinflammatory cytokines, elevated during inflammation caused by infection and/or autoimmune disorders, result in reduced clearance of drugs eliminated primarily by cytochrome P450 enzymes (CYPs). However, the effect of cytokines on hepatic drug transporter expression or activity has not been well-studied. Here, using plated human hepatocytes (PHHs; = 3 lots), we investigated the effect of interleukin (IL)-6, IL-1, tumor necrosis factor- (TNF-), and interferon-γ (IFN-γ), on the mRNA expression and activity of hepatic drug transporters.

Dysregulation of the mRNA Expression of Human Renal Drug Transporters by Proinflammatory Cytokines in Primary Human Proximal Tubular Epithelial Cells.

Proinflammatory cytokines, which are elevated during inflammation or infections, can affect drug pharmacokinetics (PK) due to the altered expression or activity of drug transporters and/or metabolizing enzymes. To date, such studies have focused on the effect of cytokines on the activity and/or mRNA expression of hepatic transporters and drug-metabolizing enzymes. However, many antibiotics and antivirals used to treat infections are cleared by renal transporters, including the basal organic cation transporter 2 (OCT2), organic anion transporters 1 and 3 (OAT1 and 3), the apical multidrug and toxin extrusion proteins 1 and 2-K (MATE1/2-K), and multidrug resistance-associated protein 2 and 4 (MRP2/4).

An update on placental drug transport and its relevance to fetal drug exposure.

Pregnant women are often complicated with diseases that require treatment with medication. Most drugs administered to pregnant women are off-label without the necessary dose, efficacy, and safety information. Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.

SLC20a1/PiT-1 is required for chorioallantoic placental morphogenesis.

The placenta mediates the transport of nutrients, such as inorganic phosphate (Pi), between the maternal and fetal circulatory systems. The placenta itself also requires high levels of nutrient uptake as it develops to provide critical support for fetal development. This study aimed to determine placental Pi transport mechanisms using in vitro and in vivo models.

Maternal and Fetal Exposure to (-)-Δ-tetrahydrocannabinol and Its Major Metabolites in Pregnant Mice Is Differentially Impacted by P-glycoprotein and Breast Cancer Resistance Protein.

(-)-Δ-tetrahydrocannabinol (THC) is the primary pharmacological active constituent of cannabis. 11-hydroxy-THC (11-OH-THC) and 11--9-carboxy-THC (THC-COOH) are respectively the active and nonactive circulating metabolites of THC in humans. While previous animal studies reported that THC could be a substrate of mouse P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), we have shown, , that only THC-COOH is a weak substrate of human BCRP, but not of P-gp.

Glycolysis aggravates methotrexate toxicity by fueling RFC1-controlled intestinal absorption in rheumatic rats.

Methotrexate (MTX) is a first line anti-rheumatic drug. This study was designed to investigate the impact of rheumatoid arthritis (RA) conditions on its oral absorption, and clarify the relevance with changes of MTX absorption-related transporters in rheumatic models. MTX was orally administered to healthy, collagen-induced arthritis (CIA), and adjuvant-induced arthritis (AIA) rats.

Tetrahydrocannabinol and Its Major Metabolites Are Not (or Are Poor) Substrates or Inhibitors of Human P-Glycoprotein [ATP-Binding Cassette (ABC) B1] and Breast Cancer Resistance Protein (ABCG2).

(-)-Δ-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis. In humans, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) are psychoactive and nonpsychoactive circulating metabolites of THC, respectively. Whether these cannabinoids are substrates or inhibitors of human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) is unknown.

Key hepatic metabolic pathways are altered in germ-free mice during pregnancy.

Pregnancy is associated with metabolic changes to accommodate the mother and her growing fetus. The microbiome has been shown to modulate host metabolism of endogenous and exogenous substances. However, the combined effects of pregnancy and the microbiome on host metabolism have not been investigated.

Gestational Age-Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics.

Some women take medication during pregnancy to address a variety of clinical conditions. Because of ethical and logistical concerns, it is impossible to determine fetal drug exposure, and therefore fetal risk, during pregnancy. Hence, alternative approaches need to be developed to predict maternal-fetal drug exposure throughout pregnancy.

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy.

The microbiome and pregnancy are known to alter drug disposition, yet the interplay of the two physiologic factors on the expression and/or activity of drug metabolizing enzymes and transporters (DMETs) is unknown. This study investigated the effects of microbiome on host hepatic DMETs in mice during pregnancy by comparing four groups of conventional (CV) and germ-free (GF) female mice and pregnancy status, namely, CV nonpregnant, GF non-pregnant, CV pregnant, and GF pregnant mice. Transcriptomic and targeted proteomics of hepatic DMETs were profiled by using multiomics.

Marijuana-derived cannabinoids inhibit uterine endometrial stromal cell decidualization and compromise trophoblast-endometrium cross-talk.

Marijuana (cannabis) use by pregnant women in the United States is increasing and there is a dire need to understand the beneficial or harmful effects of cannabis during pregnancy. Uterine endometrial stromal cells are fibroblast-like cells that differentiate into secretory cells, a process called decidualization, to create a microenvironment conducive for placenta formation and early embryonic growth. In this study, using model human cell lines, we for the first time demonstrate that Δ-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) inhibit endometrial stromal cell decidualization and have adverse effects on trophoblast-endometrium cross-talk.

Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines.

Background: Bupropion (BUP) is widely used as an antidepressant and smoking cessation aid. There are three major pharmacologically active metabolites of BUP, Erythrohydrobupropion (EB), Hydroxybupropion (OHB) and Threohydrobupropion (TB). At present, the mechanisms underlying the overall disposition and systemic clearance of BUP and its metabolites have not been well understood, and the role of transporters has not been studied.

Metabolomics Analysis Reveals Therapeutic Effects of α-Mangostin on Collagen-Induced Arthritis in Rats by Down-regulating Nicotinamide Phosphoribosyltransferase.

α-Mangostin (MAN) is a bioactive compound isolated from pericarp of mangosteen (Garcinia mangostana Linn.) with significant anti-rheumatic potentials. The purpose of this study was to explore the mechanisms underlying its therapeutic effects on collagen-induced arthritis (CIA) in rats with metabolomics approaches.

-Mangostin Alleviated Lipopolysaccharide Induced Acute Lung Injury in Rats by Suppressing NAMPT/NAD Controlled Inflammatory Reactions.

-Mangostin (MAN) is a bioactive xanthone isolated from mangosteen. This study was designed to investigate its therapeutic effects on acute lung injury (ALI) and explore the underlying mechanisms of action. Rats from treatment groups were subject to oral administration of MAN for 3 consecutive days beforehand, and then ALI was induced in all the rats except for normal controls via an intraperitoneal injection with lipopolysaccharide.

An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus.

P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are highly expressed in the placenta and fetus throughout gestation and can modulate exposure and toxicity of drugs and xenobiotics to the vulnerable fetus during the sensitive times of growth and development. We aim to provide an update on current knowledge on placental and fetal expressions of the two transporters in different species, and to provide insight on interpreting transporter expression and fetal exposure relative to the concept of fraction of drug transported. Areas covered: Comprehensive literature review through PubMed (primarily from July 2010 to February 2018) on P-gp and BCRP expression and function in the placenta and fetus of primarily human, mouse, rat, and guinea pig.

Temporal transcriptomic analysis of metabolic genes in maternal organs and placenta during murine pregnancy.

Maternal pregnancy adaptation is crucial for fetal development and long-term health. Complex interactions occur between maternal digestive and excretory systems as they interface with the developing fetus through the placenta, and transcriptomic regulation in these organs throughout pregnancy is poorly understood. Our objective is to characterize transcriptomic changes across gestation in maternal organs and placenta.

Quantitative Proteomics Reveals Changes in Transporter Protein Abundance in Liver, Kidney and Brain of Mice by Pregnancy.

Background: Few studies have systematically investigated pregnancy-induced changes in protein abundance of drug transporters in organs important for drug/xenobiotic disposition.

Objective: The goal of this study was to compare protein abundance of important drug/xenobiotic transporters including Abcb1a, Abcg2, Abcc2, and Slco1b2 in the liver, kidney and brain of pregnant mice on gestation day 15 to that of non-pregnant mice.

Methods: The mass spectrometry-based proteomics was used to quantify changes in protein abundance of transporters in tissues from pregnant and non-pregnant mice.

Marijuana use differentially affects cannabinoid receptor expression in early gestational human endometrium and placenta.

Marijuana is one of the most abused drugs among pregnant women leading to maternal and fetal abnormalities. Cannabinoids are the active ingredients of marijuana, which interact with cannabinoid receptors such as CNR1 and CNR2 to activate cellular signaling pathways. Human endometrium and placenta are known to express CNR1 and CNR2 and can respond to cannabinoid signaling.

Drug Transporters in Xenobiotic Disposition and Pharmacokinetic Prediction.

Drug transporters are widely expressed in organs and tissue barriers throughout human and animal bodies. Studies over the last two decades have identified various ATP-binding cassette and solute carrier transporters that play critical roles in the absorption, distribution, metabolism, and elimination of drugs and xenobiotics. This special section contains more than 20 original manuscripts and reviews that cover the most recent advances in the areas of drug transporter research, including the basic biology and function of transporters, expression of drug transporters in organ and tissue barriers, the mechanisms underlying regulation of transporter expression, transporter-mediated drug disposition in animal models, and the development and utilization of new technologies in drug transporter study, as well as pharmacokinetic modeling and simulation to assess transporter involvement in drug disposition and drug-drug interactions.

Hepatic Transport of 25-Hydroxyvitamin D Conjugates: A Mechanism of 25-Hydroxyvitamin D Delivery to the Intestinal Tract.

Vitamin D is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25-Hydroxyvitamin D (25OHD), the most abundant circulating metabolite of vitamin D, is further transformed to the biologically active metabolite 1,25-dihydroxyvitamin D (1,25-(OH)D) by CYP27B1 in the kidney and extrarenal tissues, and to nonactive metabolites by other cytochrome P450 enzymes. In addition, 25OHD undergoes sulfation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD-3--sulfate (25OHD-S) and 25OHD-3--glucuronide (25OHD-G), both of which were detected in human blood and bile.

Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D-3--Sulfate, a Major Circulating Vitamin D Metabolite in Humans.

Metabolism of 25-hydroxyvitamin D (25OHD) plays a central role in regulating the biologic effects of vitamin D in the body. Although cytochrome P450-dependent hydroxylation of 25OHD has been extensively investigated, limited information is available on the conjugation of 25OHD In this study, we report that 25OHD is selectively conjugated to 25OHD-3--sulfate by human sulfotransferase 2A1 (SULT2A1) and that the liver is a primary site of metabolite formation. At a low (50 nM) concentration of 25OHD, 25OHD-3--sulfate was the most abundant metabolite, with an intrinsic clearance approximately 8-fold higher than the next most efficient metabolic route.

Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation.

Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP's analgesic activity and 10 times BUP's respiratory depression effect. To optimize BUP's dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection.

Digging Deeper into CYP3A Testosterone Metabolism: Kinetic, Regioselectivity, and Stereoselectivity Differences between CYP3A4/5 and CYP3A7.

The metabolism of testosterone to 6-hydroxytestosterone (6-OH-T) is a commonly used assay to evaluate human CYP3A enzyme activities. However, previous reports have indicated that CYP3A7 also produces 2-hydroxytestosterone (2-OH-T) and that a 2-OH-T/6-OH-T ratio may be a unique endogenous biomarker of the activity of the enzyme. Until now, the full metabolite and kinetic profile for testosterone hydroxylation by CYP3A7 has not been fully examined.