Uptake Transport at the BBB—Examples and SAR

Cheng, Ziqiang; Liu, Qian

doi:10.1002/9781118788523.ch7

Cited by 3 publications

(3 citation statements)

References 37 publications

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“…One of the challenges for using LAT1 as a delivery tool has been the competition of the transported drugs with endogenous amino acids substrates, which have millimolar concentrations in the plasma. , For example, it has been shown that brain uptake of L-DOPA decreases after a meal rich in large amino acids, and L-DOPA decreases the concentration of other amino acids (i.e., tyrosine and tryptophan) in the rat brain . Potential antagonism by endogenous amino acids has been cited as a limitation for using this transporter in drug delivery . One possible way to overcome this problem is by increasing the affinity of drugs or prodrugs for the transporter relative to natural amino acid substrates ( K m = 11–210 μM) .…”

Section: Introductionmentioning

confidence: 99%

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

et al. 2018

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The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

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Section: Introductionmentioning

confidence: 99%

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

et al. 2018

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“…Although both OATP1A2 and OATP2B1 have been implicated in the transport of neuroactive steroids and various exogenous compounds including statins, antidiabetics, antihistamines, and central active drugs like triptans [ 61 ], there are still subtle differences between them. OATP1A2 exhibits broad substrate specificity for the BBB, while OATP2B1 has a relatively narrower substrate specificity [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…OATP1A2 and OATP2B1 are considered to be the most abundant OA OATP1A2 is predominantly localized on the apical side of the brain capi cells, while OATP2B1 is primarily distributed on the basolateral sides both OATP1A2 and OATP2B1 have been implicated in the transport of n oids and various exogenous compounds including statins, antidiabetics and central active drugs like triptans [61], there are still subtle difference OATP1A2 exhibits broad substrate specificity for the BBB, while OATP tively narrower substrate specificity [62].…”

Section: Discussionmentioning

confidence: 99%

The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood–Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms

Jiang,

Luo,

Zhang

et al. 2024

Pharmaceutics

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Background: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. Methods: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood–brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. Results: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H+/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. Conclusions: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood–brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood–brain barrier metabolism and transport of active glucuronide conjugates.

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Impact of In Vitro Passive Permeability in a P-gp-transfected LLC-PK1 Model on the Prediction of the Rat and Human Unbound Brain-to-Plasma Concentration Ratio

et al. 2020

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Uptake Transport at the BBB—Examples and SAR

Cited by 3 publications

References 37 publications

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood–Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms

Impact of In Vitro Passive Permeability in a P-gp-transfected LLC-PK1 Model on the Prediction of the Rat and Human Unbound Brain-to-Plasma Concentration Ratio

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