A Perspective on Efflux Transport Proteins in the Liver

Detailed knowledge regarding the influence of hepatic transport proteins on drug disposition has advanced at a rapid pace over the past decade. Efflux transport proteins located in the basolateral and apical (canalicular) membranes of hepatocytes play an important role in the hepatic elimination of many endogenous and exogenous compounds, including drugs and metabolites. This review focuses on the role of these efflux transporters in hepatic drug excretion. The impact of these proteins as underlying factors for disease is highlighted, and the importance of hepatic efflux proteins in the efficacy and toxicity of drugs is discussed. In addition, a brief overview of methodology to evaluate the function of hepatic efflux transport proteins is provided. Current challenges in predicting the impact of altered efflux protein function on systemic, intestinal and hepatocyte exposure to drugs and metabolites are highlighted

Systems Pharmacology Modeling Predicts Delayed Presentation and Species Differences in Bile Acid–Mediated Troglitazone Hepatotoxicity

Troglitazone (TGZ) caused delayed, life-threatening drug-induced liver injury (DILI) in some patients, but was not hepatotoxic in rats. This study investigated altered bile acid (BA) homeostasis as a mechanism of TGZ hepatotoxicity using a systems pharmacology model incorporating drug/metabolite disposition, BA physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers. In the simulated human population, TGZ (200–600mg/day×6months) resulted in delayed increases in serum ALT>3× ULN in 0.3–5.1% of the population with concomitant bilirubin elevations>2× ULN in 0.3–3.6%. In contrast, pioglitazone (15–45mg/day×6months) did not elicit hepatotoxicity, consistent with clinical data. TGZ was not hepatotoxic in the simulated rat population. In summary, mechanistic modeling based only on BA effects accurately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity, and the relative liver safety of pioglitazone. Systems pharmacology models integrating physiology and experimental data can evaluate DILI mechanisms and may be useful to predict hepatotoxic potential of drug candidates

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation

Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK)

Development of a Population Pharmacokinetic Model To Describe Azithromycin Whole-Blood and Plasma Concentrations over Time in Healthy Subjects

ABSTRACT Azithromycin (AZI), a broad-spectrum antibiotic, accumulates in polymorphonuclear cells and peripheral blood mononuclear cells. The distribution of AZI in proinflammatory cells may be important to the anti-inflammatory properties. Previous studies have described plasma AZI pharmacokinetics. The objective of this study was to describe the pharmacokinetics of AZI in whole blood (concentration in whole blood [ C b ]) and plasma (concentration in plasma [ C p ]) of healthy subjects. In this study, 12 subjects received AZI (500 mg once a day for 3 days). AZI C b and C p were quantified in serial samples collected up to 3 weeks after the last dose and analyzed using noncompartmental and compartmental methods. After the last dose, C b was greater than C p . Importantly, C b , but not C p , was quantifiable in all but one subject at 3 weeks. The blood area under the curve during a 24-h dosing interval (AUC 24 ) was ∼2-fold greater than the plasma AUC 24 , but simulations suggested that C b was not at steady state by day 3. Upon exploration of numerous models, an empirical 3-compartment model adequately described C p and C b , but C p was somewhat underestimated. Intercompartmental clearance (CL; likely representing cells) was lower than apparent oral CL (18 versus 118 liters/h). Plasma, peripheral, and cell compartmental volumes were 439 liters, 2,980 liters, and 3,084 liters, respectively. Interindividual variability in CL was low (26.2%), while the volume of distribution variability was high (107%). This is the first report to describe AZI C b in healthy subjects, the distribution parameters between C p and C b , and AZI retention in blood for up to 3 weeks following 3 daily doses. The model can be used to predict C b from C p for AZI under various dosing regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01026064.

Use of cassette dosing in sandwich-cultured rat and human hepatocytes to identify drugs that inhibit bile acid transport

Hepatocellular accumulation of bile acids due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) is one proposed mechanism of drug-induced liver injury (DILI). Some hepatotoxic compounds also are potent inhibitors of bile acid uptake by Na+-dependent taurocholate cotransporting polypeptide (NTCP/SLC10A1). This study used a cassette dosing approach in rat and human sandwich-cultured hepatocytes (SCH) to determine whether known or suspected hepatotoxic drugs inhibit bile acid transport individually or in combination. [3H]-Taurocholate served as the NTCP/BSEP probe substrate. Individually, cyclosporin A and rifampin decreased taurocholate in vitro biliary clearance (Clbiliary) and biliary excretion index (BEI) by more than 20% in rat SCH, suggesting that these drugs primarily inhibited canalicular efflux. In contrast, ampicillin, carbenicillin, cloxacillin, nafcillin, oxacillin, carbamazepine, pioglitazone, and troglitazone decreased the in vitro Clbiliary by more than 20% with no notable change in BEI, suggesting that these drugs primarily inhibited taurocholate uptake. Cassette dosing (n=2–4 compounds per cassette) in rat SCH yielded similar findings, and results in human SCH were consistent with rat SCH. In summary, cassette dosing in SCH is a useful in vitro approach to identify compounds that inhibit the hepatic uptake and/or excretion of bile acids, which may cause DILI

Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis

The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically-derived morphine glucuronide (morphine-3- and morphine-6-glucuronide), and fasting bile acids was evaluated in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225nM and 58.8 vs. 37.2μM*min, respectively; P≤0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0-last (P<0.001). Fasting serum glycocholate, taurocholate and total bile acid concentrations were associated with NASH severity (P<0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population

Bosonic Excitations in Random Media

We consider classical normal modes and non-interacting bosonic excitations in disordered systems. We emphasise generic aspects of such problems and parallels with disordered, non-interacting systems of fermions, and discuss in particular the relevance for bosonic excitations of symmetry classes known in the fermionic context. We also stress important differences between bosonic and fermionic problems. One of these follows from the fact that ground state stability of a system requires all bosonic excitation energy levels to be positive, while stability in systems of non-interacting fermions is ensured by the exclusion principle, whatever the single-particle energies. As a consequence, simple models of uncorrelated disorder are less useful for bosonic systems than for fermionic ones, and it is generally important to study the excitation spectrum in conjunction with the problem of constructing a disorder-dependent ground state: we show how a mapping to an operator with chiral symmetry provides a useful tool for doing this. A second difference involves the distinction for bosonic systems between excitations which are Goldstone modes and those which are not. In the case of Goldstone modes we review established results illustrating the fact that disorder decouples from excitations in the low frequency limit, above a critical dimension $d_c$, which in different circumstances takes the values $d_c=2$ and $d_c=0$. For bosonic excitations which are not Goldstone modes, we argue that an excitation density varying with frequency as $\rho(\omega) \propto \omega^4$ is a universal feature in systems with ground states that depend on the disorder realisation. We illustrate our conclusions with extensive analytical and some numerical calculations for a variety of models in one dimension

Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group

The critical importance of membrane-bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented

Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver

Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed

In Vivo Alterations in Drug Metabolism and Transport Pathways in Patients with Chronic Kidney Diseases

This study was designed to prospectively evaluate the in vivo activities of drug transporters, metabolizing enzymes and pharmacokinetics in patients with chronic kidney diseases (CKD) caused by glomerulonephritis and non-glomerular etiologies