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Transporters in Drug and Xenobiotic Disposition

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 16155

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Special Issue Editor

Prof. Dr. Abby C. Collier

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Guest Editor

Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Interests: ABC transporters; drug disposition; drug–drug interactions; drug resistance; excretion; membrane dynamics; organic anion transporters; organic cation transporters; pharmacokinetics; privileged sites of drug action; solute carrier transporters

Special Issue Information

Dear Colleagues,

Transporters play critical roles in drug and xenobiotic disposition. The tissue distribution of these transporters varies by role, and important advances in drug and chemical safety have been attributed to better understanding of transporter localization, expression and activities. In addition to parent drug disposition, transporters are also vital to the disposition of primary and secondary metabolites, such as facilitating excretion and contributing to enterohepatic re-circulation. Integrating functional transporter studies into disposition and pharmacokinetic considerations has been difficult in the past, but new approaches and models are increasingly allowing consideration of transporters’ functional dynamics. This Special Issue will cover transporter dynamics in drug and xenobiotic disposition, with particular attention to effects on pharmacokinetics/toxicokinetics.

Prof. Dr. Abby C. Collier
Guest Editor

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Keywords

ABC transporters
drug disposition
drug–drug interactions
drug resistance
excretion
membrane dynamics
organic anion transporters
organic cation transporters
pharmacokinetics
privileged sites of drug action
solute carrier transporters

Published Papers (6 papers)

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Research

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21 pages, 2715 KiB

Open AccessArticle

Generation of a hTERT-Immortalized Human Sertoli Cell Model to Study Transporter Dynamics at the Blood-Testis Barrier

by Raymond K. Hau, Siennah R. Miller, Stephen H. Wright and Nathan J. Cherrington

Pharmaceutics 2020, 12(11), 1005; https://doi.org/10.3390/pharmaceutics12111005 - 22 Oct 2020

Cited by 10 | Viewed by 2117

Abstract

The blood-testis barrier (BTB) formed by adjacent Sertoli cells (SCs) limits the entry of many chemicals into seminiferous tubules. Differences in rodent and human substrate-transporter selectivity or kinetics can misrepresent conclusions drawn using rodent in vitro models. Therefore, human in vitro models are preferable when studying transporter dynamics at the BTB. This study describes a hTERT-immortalized human SC line (hT-SerC) with significantly increased replication capacity and minor phenotypic alterations compared to primary human SCs. Notably, hT-SerCs retained similar morphology and minimal changes to mRNA expression of several common SC genes, including AR and FSHR. The mRNA expression of most xenobiotic transporters was within the 2-fold difference threshold in RT-qPCR analysis with some exceptions (OAT3, OCT3, OCTN1, OATP3A1, OATP4A1, ENT1, and ENT2). Functional analysis of the equilibrative nucleoside transporters (ENTs) revealed that primary human SCs and hT-SerCs predominantly express ENT1 with minimal ENT2 expression at the plasma membrane. ENT1-mediated uptake of [³H] uridine was linear over 10 min and inhibited by NBMPR with an IC₅₀ value of 1.35 ± 0.37 nM. These results demonstrate that hT-SerCs can functionally model elements of transport across the human BTB, potentially leading to identification of other transport pathways for xenobiotics, and will guide drug discovery efforts in developing effective BTB-permeable compounds. Full article

(This article belongs to the Special Issue Transporters in Drug and Xenobiotic Disposition)

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13 pages, 1244 KiB

Open AccessArticle

Completing the Enalaprilat Excretion Pathway—Renal Handling by the Proximal Tubule

by Nori J. L. Smeets, Carlijn H. C. Litjens, Jeroen J. M. W. van den Heuvel, Hedwig van Hove, Petra van den Broek, Frans G. M. Russel, Jan B. Koenderink and Saskia N. de Wildt

Pharmaceutics 2020, 12(10), 935; https://doi.org/10.3390/pharmaceutics12100935 - 30 Sep 2020

Cited by 4 | Viewed by 2135

Abstract

Background: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. Methods: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. Results: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520–770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. Conclusion: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug–drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates. Full article

(This article belongs to the Special Issue Transporters in Drug and Xenobiotic Disposition)

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18 pages, 4942 KiB

Open AccessArticle

Characterization of the Blood–Brain Barrier Integrity and the Brain Transport of SN-38 in an Orthotopic Xenograft Rat Model of Diffuse Intrinsic Pontine Glioma

by Catarina Chaves, Xavier Declèves, Meryam Taghi, Marie-Claude Menet, Joelle Lacombe, Pascale Varlet, Nagore G. Olaciregui, Angel M. Carcaboso and Salvatore Cisternino

Pharmaceutics 2020, 12(5), 399; https://doi.org/10.3390/pharmaceutics12050399 - 27 Apr 2020

Cited by 17 | Viewed by 4070

Abstract

The blood–brain barrier (BBB) hinders the brain delivery of many anticancer drugs. In pediatric patients, diffuse intrinsic pontine glioma (DIPG) represents the main cause of brain cancer mortality lacking effective drug therapy. Using sham and DIPG-bearing rats, we analyzed (1) the brain distribution of 3-kDa-Texas red-dextran (TRD) or [¹⁴C]-sucrose as measures of BBB integrity, and (2) the role of major ATP-binding cassette (ABC) transporters at the BBB on the efflux of the irinotecan metabolite [³H]-SN-38. The unaffected [¹⁴C]-sucrose or TRD distribution in the cerebrum, cerebellum, and brainstem regions in DIPG-bearing animals suggests an intact BBB. Targeted proteomics retrieved no change in P-glycoprotein (P-gp), BCRP, MRP1, and MRP4 levels in the analyzed regions of DIPG rats. In vitro, DIPG cells express BCRP but not P-gp, MRP1, or MRP4. Dual inhibition of P-gp/Bcrp, or Mrp showed a significant increase on SN-38 BBB transport: Cerebrum (8.3-fold and 3-fold, respectively), cerebellum (4.2-fold and 2.8-fold), and brainstem (2.6-fold and 2.2-fold). Elacridar increased [³H]-SN-38 brain delivery beyond a P-gp/Bcrp inhibitor effect alone, emphasizing the role of another unidentified transporter in BBB efflux of SN-38. These results confirm a well-preserved BBB in DIPG-bearing rats, along with functional ABC-transporter expression. The development of chemotherapeutic strategies to circumvent ABC-mediated BBB efflux are needed to improve anticancer drug delivery against DIPG. Full article

(This article belongs to the Special Issue Transporters in Drug and Xenobiotic Disposition)

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14 pages, 1533 KiB

Open AccessArticle

Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F_2α: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model

by Robert S. Jones, Mark D. Parker and Marilyn E. Morris

Pharmaceutics 2020, 12(3), 201; https://doi.org/10.3390/pharmaceutics12030201 - 26 Feb 2020

Cited by 9 | Viewed by 2486

Abstract

Monocarboxylate transporter 6 (MCT6; SLC16A5) is a recently studied drug transporter that currently has no annotated endogenous function. Currently, only a handful of compounds have been characterized as substrates for MCT6 (e.g., bumetanide, nateglinide, probenecid, and prostaglandin F_2α (PGF2α)). The objective of our research was to characterize the MCT6-specific transporter kinetic parameters and MCT6-specific in vitro and in vivo interactions of PGF2α. Murine and human MCT6-mediated transport of PGF2α was assessed in MCT6-transfected oocytes. Additionally, endogenous PGF2α and a primary PGF2α metabolite (PGFM) were measured in plasma and urine in Mct6 knockout (Mct6^−/−) and wild-type (Mct6^+/+) mice. Results demonstrated that the affinity was approximately 40.1 and 246 µM respectively, for mouse and human, at pH 7.4. In vivo, plasma PGF2α concentrations in Mct6^−/− mice were significantly decreased, compared to Mct6^+/+ mice (3.3-fold). Mct6^-/- mice demonstrated a significant increase in urinary PGF2α concentrations (1.7-fold). A similar trend was observed with plasma PGFM concentrations. However, overnight fasting resulted in significantly increased plasma PGF2α concentrations, suggesting a diet-dependent role of Mct6 regulation on the homeostasis of systemic PGF2α. Overall, these results are the first to suggest the potential regulatory role of MCT6 in PGF2α homeostasis, and potentially other PGs, in distribution and metabolism. Full article

(This article belongs to the Special Issue Transporters in Drug and Xenobiotic Disposition)

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11 pages, 6045 KiB

Open AccessArticle

Impact of Viral Inflammation on the Expression of Renal Drug Transporters in Pregnant Rats

by Navaz Karimian Pour, Eliza R. McColl and Micheline Piquette-Miller

Pharmaceutics 2019, 11(12), 624; https://doi.org/10.3390/pharmaceutics11120624 - 22 Nov 2019

Cited by 12 | Viewed by 2977

Abstract

Inflammation impacts the expression and function of drug transporters at term-gestation; however, the impact of inflammation on the expression of drug transporters at mid-gestation is largely unknown. Since renal drug transporters play a key role in the clearance of many drugs prescribed during pregnancy, our objective was to study the impact of the viral mimetic poly I:C on the expression of renal transporters in pregnant rats at mid-gestation. Poly I:C (10 mg/kg) or saline was administered intraperitoneally to pregnant Sprague–Dawley rats on gestational day 14. Expression of renal transporters was measured at 6, 24, and 48 h by qRT-PCR and Western blot. The mRNA levels of Mdr1a, Mrp4, Oct2, Octn1, Octn2, Mate1, Oat1-3, Urat1, Oatp4c1, Ent1, and Pept2 were significantly lower in the poly I:C group at 6 h. At 24 h, only the mRNA levels of Oct2, Oatp4c1, and Ent1 were decreased compared to saline. Poly I:C significantly decreased protein expression of Urat1 at 24 h, and P-gp, Oct2, Mate1, Oat1, Oat3 at 48 h,. Poly I:C imposed significant reductions in the expression of several key renal transporters at mid-gestation in pregnant rats. Thus, viral infection may impact renal excretion of drug transporter substrates, potentially leading to drug–disease interactions. Full article

(This article belongs to the Special Issue Transporters in Drug and Xenobiotic Disposition)

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Review

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19 pages, 463 KiB

Open AccessReview

Equine Drug Transporters: A Mini-Review and Veterinary Perspective

by Brielle Rosa

Pharmaceutics 2020, 12(11), 1064; https://doi.org/10.3390/pharmaceutics12111064 - 08 Nov 2020

Cited by 3 | Viewed by 1979

Abstract

Xenobiotic transport proteins play an important role in determining drug disposition and pharmacokinetics. Our understanding of the role of these important proteins in humans and pre-clinical animal species has increased substantially over the past few decades, and has had an important impact on human medicine; however, veterinary medicine has not benefitted from the same quantity of research into drug transporters in species of veterinary interest. Differences in transporter expression cause difficulties in extrapolation of drug pharmacokinetic parameters between species, and lack of knowledge of species-specific transporter distribution and function can lead to drug–drug interactions and adverse effects. Horses are one species in which little is known about drug transport and transporter protein expression. The purpose of this mini-review is to stimulate interest in equine drug transport proteins and comparative transporter physiology. Full article

(This article belongs to the Special Issue Transporters in Drug and Xenobiotic Disposition)

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