Rosuvastatin PBPK Modeling: Incorporating Liver Concentrations and Effects of Ethnicity, Genetic Polymorphisms, Lactone Formation, DDI and Pregnancy.

Rosuvastatin (RSV), a potent HMG-CoA reductase inhibitor, is widely used for the management of hyperlipidemia and prevention of cardiovascular disease. Its absorption and disposition are primarily transporter-mediated, involving intestinal absorption by OATP2B1 and efflux by BCRP; hepatic uptake by OATP1B1, OATP1B3, OATP2B1, and NTCP; and biliary excretion by BCRP and MRP2. Given its minimal metabolism, RSV serves as a model substrate for transporter-based drug absorption, disposition, and DDI studies.

Regulation of expression and activity of hepatic transporters by pregnancy-related hormones in HepaRG cells.

Although pregnancy induces changes in in vivo hepatic metabolic activity, little is known about its effects on hepatic transporter activity. Previously, we showed that pregnancy-related hormones (PRH) induce mRNA expression and/or activity of hepatic transporters, sodium taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2 (OAT2), and organic cation transporter 1 (OCT1) in plated human hepatocytes (PHH). However, PHH cannot be readily used to determine the mechanisms of regulation of hepatic transporters by PRH.

Characterization of organic anion transporting polypeptide (OATP)1B1 and OATP1B3 humanized rat as a translational model to study the pharmacokinetics of OATP1B substrate drugs.

Organic anion transporting polypeptide (OATP)1B1 and OATP1B3 (OATP1B) are clinically important transporters that mediate active hepatic uptake for a broad range of drugs and endogenous compounds and play a pivotal role in hepatic disposition and drug-drug interactions (DDIs) of substrate drugs. Efforts have been made on developing humanized transgenic OATP1B rodent models to mechanistically understand the role of OATP1B in drug disposition and DDIs. However, the lack of robust OATP1B functional activities limits their utility.

Predicting in vivo cannabinoid-drug interactions mediated via inhibition of UDP-glucuronosyltransferases using in vitro studies and physiologically based pharmacokinetic modeling and simulations.

We previously reported the inhibitory potential of the most extensively studied cannabinoids, cannabidiol (CBD) and Δ-tetrahydrocannabinol (THC), along with their respective circulating metabolites, against a panel of cytochrome P450 (CYP) enzymes. In the current work, we characterized the inhibitory potential of these cannabinoids against a panel of recombinant human UDP-glucuronosyltransferases (UGTs). Upon screening CBD, THC, and their primary circulating metabolites (7-hydroxy CBD or 11-hydroxy THC) at 10 μM, cannabinoids likely to inhibit UGTs at pharmacologically relevant concentrations in vivo were characterized further.

Identification of selective substrates and inhibitors of the major human renal uptake transporters.

Renal clearance of drugs mediated by transporters can be affected by diseases (eg, inflammation due to infections), physiological changes (eg, pregnancy), or drug-drug interactions. To elucidate the transporters involved, the magnitude of effect, and the underlying mechanisms, human proximal tubular epithelial cells could be exposed to potential perpetrators (eg, cytokines, pregnancy-related hormones or the interacting drug), and the activity of transporters quantified. A crucial prerequisite for such studies is the identification of selective substrates or substrate-inhibitor pairs for each renal transporter.

Cannabidiol and Δ9-tetrahydrocannabinol induce drug-metabolizing enzymes, but not transporters, in human hepatocytes: Implications for predicting complex cannabinoid-drug interactions.

Cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC) can inhibit multiple CYPs and UGTs in vivo and/or in vitro. CBD, but not THC, is also a time-dependent inhibitor of CYP3A, CYP1A2, and CYP2C19. We showed that a single 640 mg oral dose of CBD inhibits oral midazolam plasma clearance by 56%, whereas others found no interaction of chronic CBD with midazolam.

Quantification and prediction of human fetal (-)-Δ-tetrahydrocannabinol/(±)-11-OH-Δ-tetrahydrocannabinol exposure during pregnancy to inform fetal cannabis toxicity.

Prenatal cannabis use is associated with neurodevelopmental deficits, likely due to exposure to the psychoactive cannabinoid, (-)-Δ-tetrahydrocannabinol, and its active metabolite, (±)-11-OH-Δ-tetrahydrocannabinol. To determine causality, preclinical studies mimicking human fetal cannabinoid exposure must be conducted. Here we show cannabinoid concentrations across gestation in maternal plasma and paired fetal tissues in trimester 1 and 2 and maternal plasma and fetal umbilical venous plasma in trimester 3.

The effect of pregnancy-related hormones on hepatic transporters: studies with premenopausal human hepatocytes.

Introduction: Pregnancy results in significant changes in drug pharmacokinetics (PK). While previous studies have elucidated the impact of pregnancy-related hormones (PRH) on mRNA or protein expression and activity of major hepatic metabolizing enzymes, their effect on hepatic drug transporters remains largely unexplored. Therefore, we investigated the effect of a cocktail of PRH on the mRNA expression and activity of hepatic transporters.

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).

Successful Prediction of Fetal Exposure to Dual BCRP/P-gp Drug Substrates Using the Efflux Ratio-Relative Expression Factor Approach and PBPK M&S.

To inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the first or second trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as K (unbound fetal umbilical venous (UV) plasma area under the curve (AUC)/unbound maternal plasma (MP) AUC), provided the observed UV/MP values, spanning the dosing interval, are available from multiple maternal-fetal dyads.

Toward improved predictions of pharmacokinetics of transported drugs in hepatic impairment: Insights from the extended clearance model.

Hepatic impairment (HI) moderately (<5-fold) affects the systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) of drugs that are substrates of the hepatic sinusoidal organic anion transporting polypeptide (OATP) transporters and are excreted unchanged in the bile and/or urine.

Interpretation of Protein-Mediated Uptake of Statins by Hepatocytes Is Confounded by the Residual Statin-Protein Complex.

Inclusion of plasma (or plasma proteins) in human hepatocyte uptake studies narrows, but does not close, the gap in in vitro to in vivo extrapolation (IVIVE) of organic anion transporting polypeptide (OATP)-mediated hepatic clearance (CL) of statins. We have previously shown that this "apparent" protein-mediated uptake effect (PMUE) of statins by OATP1B1-expressing cells, in the presence of 5% human serum albumin (HSA), is mostly an artifact caused by residual statin-HSA complex remaining in the uptake assay. We determined if the same was true with plated human hepatocytes (PHH) and if this artifact can be reduced using suspended human hepatocytes (SHH) and the oil-spin method.

Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.

Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults.

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.

A Physiologically-Based Pharmacokinetic Model for Cannabidiol in Healthy Adults, Hepatically-Impaired Adults, and Children.

Cannabidiol (CBD) is available as a prescription oral drug that is indicated for the treatment of some types of epilepsy in children and adults. CBD is also available over-the-counter and is used to self-treat a variety of other ailments, including pain, anxiety, and insomnia. Accordingly, CBD may be consumed with other medications, resulting in possible CBD-drug interactions.

Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.

Importance: Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations.

Objective: To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg).

Predicting changes in the pharmacokinetics of CYP3A-metabolized drugs in hepatic impairment and insights into factors driving these changes.

Physiologically based pharmacokinetic models, populated with drug-metabolizing enzyme and transporter (DMET) abundance, can be used to predict the impact of hepatic impairment (HI) on the pharmacokinetics (PK) of drugs. To increase confidence in the predictive power of such models, they must be validated by comparing the predicted and observed PK of drugs in HI obtained by phenotyping (or probe drug) studies. Therefore, we first predicted the effect of all stages of HI (mild to severe) on the PK of drugs primarily metabolized by cytochrome P450 (CYP) 3A enzymes using the default HI module of Simcyp Version 21, populated with hepatic and intestinal CYP3A abundance data.

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.

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.