Excretory Processes in Toxicology: Drug Transporters in Drug Development

Ness, Kp. Van; Kelly, EJ

doi:10.1016/b978-0-12-801238-3.64206-x

Cited by 3 publications

(3 citation statements)

References 107 publications

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“…Active transport is selective, requires energy expenditure and may involve transport against a concentration gradient [43]. Generally, hOCT2 substrates are hydrophilic organic cations of low molecular weight; however, the anionic prostaglandins (prostaglandin E-2 and prostaglandin F-2α) have also been identi ed as substrates of hOCT2 [44].…”

Section: Discussionmentioning

confidence: 99%

“…Generally, hOCT2 substrates are hydrophilic organic cations of low molecular weight; however, the anionic prostaglandins (prostaglandin E-2 and prostaglandin F-2α) have also been identi ed as substrates of hOCT2 [44]. Cisplatin, on the other hand, has been identi ed as both a substrate and inhibitor of hOCT2 transport [43,45]. In this study, CHs 3 and 4 showed reduced active uptake of metformin in comparison to CH-1, whilst CHs 2 and 5 demonstrated an increased rate of active uptake of metformin in comparison to CH-1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Xhosa Specific Solute Carrier Family 22-member 2 Haplotypes on the Cellular Uptake of Metformin and Cimetidine

Abrahams-October,

Kippie,

Pearce

et al. 2024

Preprint

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Background Metformin remains the cornerstone for the treatment of type 2 diabetes mellitus. Although the mechanism in which this drug elicits its therapeutic effects is unknown, studies have shown that solute carrier transporters play an important role in the transport and distribution of metformin. Genetic variation(s) in solute carrier genes have been found to play an important role in the variation of metformin efficacy and disposition observed in populations. The aim of this study was to determine the cellular uptake efficiency of metformin in SLC22A2 coding haplotypes of an indigenous South African population. Methods and Results To determine metformin and cimetidine cellular uptake in transiently transfected HEK-293 cells, an ultra high-performance liquid chromatography method was developed and used to quantitate substrate concentration(s). Haplotypes 3 and 4 showed decreased metformin uptake, and haplotypes 2 and 5 displayed increased metformin uptake in comparison to haplotype 1 (i.e. wildtype haplotype). Haplotypes 2–5 showed decreased uptake of cimetidine in comparison to haplotype 1, implying a reduced sensitivity to the inhibition of cimetidine. In all haplotypes, no significant transport was observed for metformin and cimetidine. Spearman’s correlation analysis indicated a positive but non-significant correlation (rs = 0.60; p = 0.28) across haplotypes for the active uptake of metformin and cimetidine. Passive permeability of metformin is favoured in haplotypes 3 and 5, whilst the remaining haplotypes demonstrate higher passive permeability ratios in favour of cimetidine. Conclusion Haplotype 4, which is characterised by the non-synonymous single nucleotide polymorphisms rs316019 and rs8177517, demonstrates potential impaired metformin transport.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Xhosa Specific Solute Carrier Family 22-member 2 Haplotypes on the Cellular Uptake of Metformin and Cimetidine

Abrahams-October,

Kippie,

Pearce

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…OCT2 is an uptake and secretion transporter of organic cationic substrate at physiological pH to brain, kidney, and liver and it differs from OCT1 and OCT3 in its capacity to transform (kinetic rate) low molecular weight of hydrophilic organic cationic material. Various OCT2 substrates have been characterized such as choline, dopamine, cisplatin, histamine, and others [35]. Both Abiraterone s showed a No response to OCT2 substrate beside most of their products; A-SA and A-T showed Yes to this transporter (Table 3…”

Section: Figure (6)mentioning

confidence: 99%

In Silico Taste–Toxicity Study of New Hypothetical Hetero-Abiraterone Derivatives

Khalaf¹

2022

IJOIR

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First Iraqi attempt to study drug used for prostate cancer treatment (Abiraterone) that hypothetically reacted with known chemicals classified as Anticancer drug: Tirapazamine (T) and 5-Fluorouracil (F), food additive and preservative: Butylated Hydroxy Toluene (B) and Ethoxyquin (E), and sweeteners: P-4000 (P), Sodium Cyclamate (CS), Alitame (AT), and Saccharin (SA). The second step in this work was computational study of all reactants and the formed products having newly ether, amine, and carboxylic acid ester, and sulphonate bonds by online websites. Taste, toxicity, and ADMET were calculated by three online websites related to Charite University of Medicine, Institute for Physiology, Germany and University of Melbourne, Australia. SMILES of the reactants were obtained from National Library of Medicine/ National Center for Biotechnology Information websites while products were drawn by the molecular editor CS ChemDraw Ultra and rechecked by MarvinSketch program. This in Silico study showed various results of the formed products compared to Abiraterone (A) that predicated it as sour chemical belongs to Class 4 as a harmful substance if swallowed. Abiraterone (A) toxicity on liver organ was 61% probability percentage as hepatotoxicity while carcinogenicity, Immunotoxicity, Mutagenicity, cytotoxicity, AhR, AR, Aromatase, ER, HSE, and p53 were more than 70 % to bind Progesterone or Androgen. Also, Abiraterone (A) has a poor water solubility leading to high intestinal absorption, moderate total clearance, and giving inhibition reaction to Cytochrome P450 type CYP2C19, hERG II, and Ames test. These results confirmed that Abiraterone is structurally less harmful acute class with highly chance to interact with cell components resulting lethal response. All Abiraterone hypothetical products had a harmful reaction if swelled (Class 4), sour taste. All toxicological characters may be highly affected by its water solubility and intestinal absorption towards CNS, BBB, and CaCO2 permeability, skin sensation, and Ames test issues. For example, this in Silico- QSAR foundations about Abiraterone – Saccharin (A-SA) suggest that A-SA is structurally safe and there are several possibilities of becoming an active–multiple toxicological compound.

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Effects of Xhosa specific solute carrier family 22-member 2 haplotypes on the cellular uptake of metformin and cimetidine

Abrahams-October,

Kippie,

Pearce

et al. 2025

Gene

View full text Add to dashboard Cite

Excretory Processes in Toxicology: Drug Transporters in Drug Development

Cited by 3 publications

References 107 publications

Effects of Xhosa Specific Solute Carrier Family 22-member 2 Haplotypes on the Cellular Uptake of Metformin and Cimetidine

Effects of Xhosa Specific Solute Carrier Family 22-member 2 Haplotypes on the Cellular Uptake of Metformin and Cimetidine

In Silico Taste–Toxicity Study of New Hypothetical Hetero-Abiraterone Derivatives

Effects of Xhosa specific solute carrier family 22-member 2 haplotypes on the cellular uptake of metformin and cimetidine

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