Pharmaceutical Research

Jeong, Angela; Pastor, Catherine M.; Brouwer, Kim L. R.

doi: 10.1007/s11095-023-03549-2pmid: 37349653

BackgroundUnderstanding the impact of altered hepatic uptake and/or efflux on the hepatobiliary disposition of the imaging agents [99mTc]Mebrofenin (MEB) and [153Gd]Gadobenate dimeglumine (BOPTA) is important for proper estimation of liver function.MethodsA multi-compartmental pharmacokinetic (PK) model describing MEB and BOPTA disposition in isolated perfused rat livers (IPRLs) was developed. The PK model was simultaneously fit to MEB and BOPTA concentration-time data in the extracellular space, hepatocytes, bile canaliculi, and sinusoidal efflux in livers from healthy rats, and to BOPTA concentration-time data in rats pretreated with monocrotaline (MCT).ResultsThe model adequately described MEB and BOPTA disposition in each compartment. The hepatocyte uptake clearance was much higher for MEB (55.3 mL/min) than BOPTA (6.67 mL/min), whereas the sinusoidal efflux clearance for MEB (0.000831 mL/min) was lower than BOPTA (0.0127 mL/min). The clearance from hepatocytes to bile (CLbc) for MEB (0.658 mL/min) was similar to BOPTA (0.642 mL/min) in healthy rat livers. The BOPTA CLbc was reduced in livers from MCT-pretreated rats (0.496 mL/min), while the sinusoidal efflux clearance was increased (0.0644 mL/min).ConclusionA PK model developed to characterize MEB and BOPTA disposition in IPRLs was used to quantify changes in the hepatobiliary disposition of BOPTA caused by MCT pretreatment of rats to induce liver toxicity. This PK model could be applied to simulate changes in the hepatobiliary disposition of these imaging agents in rats in response to altered hepatocyte uptake or efflux associated with disease, toxicity, or drug-drug interactions.

Smith, Logan S.; Wang, Xinwen; Shi, Jian; He, Bing; Zhu, Hao-Jie

doi: 10.1007/s11095-023-03558-1pmid: 37430149

IntroductionPolymorphisms in the Thiopurine S-Methyltransferase (TPMT) gene are associated with decreased TPMT activity, but little is known about their impact on TPMT protein expression in the liver. This project is to conduct a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with altered TPMT protein expression in human livers and to determine if demographics affect hepatic TPMT protein expression.MethodsHuman liver samples (n = 287) were genotyped using a whole genome genotyping panel and quantified for TPMT protein expression using a Data-Independent Acquisition proteomics approach.Results and DiscussionThirty-one SNPs were found to be associated with differential expression of TPMT protein in the human livers. Subsequent analysis, conditioning on rs1142345, a SNP associated with the TPMT*3A and TPMT*3C alleles, showed no additional independent signals. Mean TPMT expression is significantly higher in wildtype donors compared to those carrying the known TPMT alleles, including TPMT*3A, TPMT*3C, and TPMT*24 (0.107 ± 0.028 vs. 0.052 ± 0.014 pmol/mg total protein, P = 2.2 × 10−16). After removing samples carrying the known TPMT variants, European ancestry donors exhibited significantly higher expression than African ancestry donors (0.109 ± 0.026 vs. 0.090 ± 0.041 pmol/mg total protein, P = 0.020).ConclusionThe GWAS identified 31 SNPs associated with TPMT protein expression in human livers. Hepatic TPMT protein expression was significantly lower in subjects carrying the TPMT*3A, TPMT*3C, and TPMT*24 alleles compared to non-carriers. European ancestry was associated with significantly higher hepatic TPMT protein expression than African ancestry, independent of known TPMT variants.

Xiang, Jianming; Keep, Richard F.

doi: 10.1007/s11095-023-03550-9pmid: 37308743

This mini-review describes the role of the solute carrier (SLC)15 family of proton-coupled oligopeptide transporters (POTs) and particularly Pept2 (Slc15A2) and PhT1 (Slc15A4) in the brain. That family transports endogenous di- and tripeptides and peptidomimetics but also a number of drugs. The review focuses on the pioneering work of David E. Smith in the field in identifying the impact of PepT2 at the choroid plexus (the blood-CSF barrier) as well as PepT2 and PhT1 in brain parenchymal cells. It also discusses recent findings and future directions in relation to brain POTs including cellular and subcellular localization, regulatory pathways, transporter structure, species differences and disease states.

Chiang, Hui-Ling; Wu, Kuo-Chen; Chen, You-Yin; Ho, Chin-Jui; Wang, Han-Lin; Fu, Yu-Hua; Chen, Wen-Yu; Lin, Chun-Jung

doi: 10.1007/s11095-023-03565-2pmid: 37498500

BackgroundCerebral vascular protection is critical for stroke treatment. Adenosine modulates vascular flow and exhibits neuroprotective effects, in which brain extracellular concentration of adenosine is dramatically increased during ischemic events and ischemia-reperfusion. Since the equilibrative nucleoside transporter-2 (Ent2) is important in regulating brain adenosine homeostasis, the present study aimed to investigate the role of Ent2 in mice with cerebral ischemia-reperfusion.MethodsCerebral ischemia-reperfusion injury was examined in mice with transient middle cerebral artery occlusion (tMCAO) for 90 minutes, followed by 24-hour reperfusion. Infarct volume, brain edema, neuroinflammation, microvascular structure, regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (CMRO2), and the production of reactive oxygen species (ROS) were examined following the reperfusion.ResultsEnt2 deletion reduced the infarct volume, brain edema, and neuroinflammation in mice with cerebral ischemia-reperfusion. tMCAO-induced disruption of brain microvessels was ameliorated in Ent2−/− mice, with a reduced expression of matrix metalloproteinases-9 and aquaporin-4 proteins. Following the reperfusion, the rCBF of the wild-type (WT) mice was quickly restored to the baseline, whereas, in Ent2−/− mice, rCBF was slowly recovered initially, but was then higher than that in the WT mice at the later phase of reperfusion. The improved CMRO2 and reduced ROS level support the beneficial effects caused by the changes in the rCBF of Ent2−/− mice. Further studies showed that the protective effects of Ent2 deletion in mice with tMCAO involve adenosine receptor A2AR.ConclusionsEnt2 plays a critical role in modulating cerebral collateral circulation and ameliorating pathological events of brain ischemia and reperfusion injury.

Saleh, Mohammed A. A.; Gülave, Berfin; Campagne, Olivia; Stewart, Clinton F.; Elassaiss-Schaap, Jeroen; de Lange, Elizabeth C. M.

doi: 10.1007/s11095-023-03554-5pmid: 37442882

IntroductionThe unbound brain extracelullar fluid (brainECF) to plasma steady state partition coefficient, Kp,uu,BBB, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species.AimUse the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice.MethodsInformation on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brainECF PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brainECF.ResultsOverall, the model gave an adequate prediction of the brainECF PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brainECF data was within two-fold error limit and the other 2 drugs were within five-fold error limit.ConclusionThe current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brainECF from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.

Chu, Jessica; Panfen, Erika; Wang, Linna; Marino, Anthony; Chen, Xue-Qing; Fancher, R. Marcus; Landage, Raviraj; Patil, Omprakash; Desai, Salil Dileep; Shah, Devang; Xue, Yongjun; Sinz, Michael; Shen, Hong

doi: 10.1007/s11095-023-03563-4pmid: 37523014

PurposeThe differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition.MethodsWe assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP.ResultsECD is a potent inhibitor with a high degree of selectivity in inhibiting human P-gp (hP-gp) over human BCRP (hBCRP) (IC50s of 0.0058 ± 0.0006 vs. > 10 µM, respectively). In contrast, ECD is a potent inhibitor of rat and cynomolgus monkey BCRP (IC50 ranged from 0.059 to 0.18 µM). While the AUC of IV paclitaxel (PTX) was significantly increased by elacridar (ELD) (P < 0.05) but not ECD in rats (15 mg/kg; PO) (2.55- vs. 0.93-fold), that of PO PTX was significantly elevated to a similar extent between the inhibitors (39.5- vs. 33.5-fold). Similarly, the AUC of PO sulfasalazine (SFZ) was dramatically increased by ELD and ECD (16.6- vs. 3.04-fold) although that of IV SFZ was not significantly affected by ELD and ECD in rats (1.18- vs. 1.06-fold). Finally, a comparable ECD-induced increase of the AUC of PO talinolol in cynomolgus monkeys was observed compared with ELD (2.14- vs. 2.12-fold).ConclusionsECD may allow an in-depth appraisal of the role of intestinal efflux transporter(s) in drug disposition in animals and humans through local intestinal drug interactions.

Dong, Minlei; Li, Ping; Luo, Jun; Chen, Binxin; Jiang, Huidi

doi: 10.1007/s11095-023-03589-8pmid: 37610621

The oligopeptide/histidine transporters PHT1 and PHT2, two mammalian solute carrier family 15A proteins, mediate the transmembrane transport of histidine and some di/tripeptides via proton gradient. PHT1 and PHT2 are distributed in a variety of tissues but are preferentially expressed in immune cells and localize to the lysosome-related organelles. Studies have reported the relationships between PHT1/PHT2 and immune diseases. PHT1 and PHT2 participate in the regulation of lysosomal homeostasis and lysosome-associated signaling pathways through their transport and nontransport functions, playing important roles in inflammatory diseases. In this review, we summarize recent research on PHT1 and PHT2, aiming to provide reference for their further biological research and as targets for drug design.

Chang, Shih-Yu; Huang, Weize; Chapron, Alenka; Quiñones, Antonio J. López; Wang, Joanne; Isoherranen, Nina; Shen, Danny D.; Kelly, Edward J.; Himmelfarb, Jonathan; Yeung, Catherine K.

doi: 10.1007/s11095-023-03594-xpmid: 37704895

BackgroundDose modification of renally secreted drugs in patients with chronic kidney disease (CKD) has relied on serum creatinine concentration as a biomarker to estimate glomerular filtration (GFR) under the assumption that filtration and secretion decline in parallel. A discrepancy between actual renal clearance and predicted renal clearance based on GFR alone is observed in severe CKD patients with tenofovir, a compound secreted by renal OAT1/3. Uremic solutes that inhibit OAT1/3 may play a role in this divergence.MethodsTo examine the impact of transporter inhibition by uremic solutes on tenofovir renal clearance, we determined the inhibitory potential of uremic solutes hippuric acid, indoxyl sulfate, and p-cresol sulfate. The inhibition parameters (IC50) were incorporated into a previously validated mechanistic kidney model; simulated renal clearance and plasma PK profile were compared to data from clinical studies.ResultsWithout the incorporation of uremic solute inhibition, the PBPK model failed to capture the observed data with an absolute average fold error (AAFE) > 2. However, when the inhibition of renal uptake transporters and uptake transporters in the slow distribution tissues were included, the AAFE value was within the pre-defined twofold model acceptance criterion, demonstrating successful model extrapolation to CKD patients.ConclusionA PBPK model that incorporates inhibition by uremic solutes has potential to better predict renal clearance and systemic disposition of secreted drugs in patients with CKD. Ongoing research is warranted to determine if the model can be expanded to include other OAT1/3 substrate drugs and to evaluate how these findings can be translated to clinical guidance for drug selection and dose optimization in patients with CKD.