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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Transporters are important in relation to the distribution of a drug. P-glyco-protein, a member of the ATP-binding family of transporters that functions as an efflux transporter capable of extruding selected toxins and xenobiotics is one such example. The expression and localisation of P-glycoprotein in specific tissues facilitate its ability to limit cellular uptake of xenobiotic substrates to these sites (e.g., the blood-brain barrier, hepatocytes, renal tubular cells, and enterocytes [13]. There are limited data on the ontogeny of the expression of P-glycoprotein in humans. They suggest a pattern of localisation in neonates similar to that in adults, but with lower level of expression.
Disorders of creatine synthesis or transport
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
CRTR deficiency is coded for by a gene on the X chromosome Xq28 [21]. CRTR mutations have included missense, nonsense, and single amino acid deletions [3, 7] (see: http://www.LOVD.nl/SLC6A8). However, large deletions, such as Arg514 to ter have been reported [3]. The frequency of mutations in the SLC6A8 gene has been compared to that of the fragile X mutation [7, 15]. Patients with mutations in SLC6A8 have been shown to have defective uptake of creatine in cultured fibroblasts [3, 7, 22]. Four missense mutations showed residual activity of the transporter and appeared to lead to a milder and more variable phenotype [7].
Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
Small molecules can penetrate the cell membrane through two major processes: passive diffusion and carrier-mediated transport [36]. In general, lipophilic substances have high membrane permeability and move across the cell membrane down their concentration gradients without a need for energy input. Hydrophilic substances, on the other hand, have low membrane permeability, and their efficient uptake into the cell requires a carrier-mediated transport. The latter must be coupled to an energy source to power the uphill transport of a given compound against its concentration gradient. In addition, carrier-mediated transport is saturable, inhibitable, and depends on the specific properties of the transporters expressed in a given tissue or cell type. Clinically, transporters are of great attraction for the development of specific drugs and also for understanding interindividual variability in drug responsiveness.
Rutaecarpine enhances the anti-diabetic activity and hepatic distribution of metformin via up-regulation of Oct1 in diabetic rats
Published in Xenobiotica, 2021
Xian-Mei Song, Bing-Jie Li, Yan-Yan Zhang, Wen-Jing Ge, She-Feng Zhang, Wei-Feng Cui, Geng-Sheng Li, Rui-Feng Liang
Metformin lowers blood glucose concentration via decreasing gluconeogenesis and glycogenolysis in the liver and has been recommended as a first-line treatment for patients with type 2 diabetes (Madiraju et al.2018, Palmer and Strippoli 2018). The liver is the main pharmacological target organ of metformin to inhibit glucose production. Metformin is taken up in the liver by organic cation transporter 1(human OCT1 and rat Oct1) and excreted from the liver into bile by multidrug and toxin extrusion protein 1 (human MATE1 and rat Mate1). Metformin is also transported into the kidney through OCTs (rat Octs) and then excreted from the kidney into urine by MATE1 (rat Mate1) and MATE2-K. These transporters involved in metformin uptake and efflux influence its systemic exposure and antihyperglycaemic activity (Liang and Giacomini 2017, Chan et al.2018). In drug-drug interactions, transporters play important roles in changing the absorption, distribution, and elimination of drugs, leading to altered pharmacokinetics and pharmacological actions (Gessner et al.2019). Several studies of metformin-drug interaction have confirmed that metformin distribution and systemic exposure could be changed through transporters (Elsby et al.2017, Li et al.2018).
Basic physiology of the blood-brain barrier in health and disease: a brief overview
Published in Tissue Barriers, 2021
The barrier type endothelial cells of the brain capillaries express certain efflux transporters, designated as multidrug-resistance transporters localized predominantly on the luminal plasma membrane.46,47 These transporters include P-gp, also called mdr-1, and breast cancer resistance protein which extrude the administered xenobiotics, compounds that include lipophilic and cationic drugs, from the brain capillary endothelial cells back to the circulation and hence reduce the delivery of drugs into the brain parenchyma at effective doses thereby posing an obstacle to the treatment of neurodegenerative disorders/diseases. A number of chemical compounds and chemotherapeutic agents used in daily clinical practice have been described as the substrates of these transporters.48,49 Successful management of tumors and refractory epilepsy is reported to be overwhelmed by the activity of P-gp.50,51 Although inhibitors of P-gp and breast cancer resistance protein have been used effectively to overcome the drug resistance in experimental animals, human data are still lacking.52–54
Effect of cyclosporine a and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation
Published in Xenobiotica, 2020
Guangting Zeng, Lihong Shi, Huilan Li, Linlin Wang, Miaomiao Zhu, Jia Luo, Zanling Zhang
VCZ is primarily metabolized by CYP2C19 (Amsden & Gubbins, 2017). In different populations, the distribution frequency of enzyme phenotypes is inconsistent, only about 3-5% of Caucasians and Africans are poor metabolism, but up to 20% of Asians are poor metabolism (Dorji et al., 2019). This means that Asians who take VCZ are more subjected to drug accumulation and adverse reactions. At present, there have been many studies about influence of gene polymorphism on plasma concentration of VCZ, however, these studies often examine the effects of genetic polymorphism of a single enzyme or transport protein, which can obscure the true pharmacogenomics complexity (Amsden & Gubbins, 2017). The genetic polymorphisms of transporters have always been closely concerned with drug transport and metabolism. A clinical retrospective study in children found that the genetic polymorphisms of ABCG2 and ABCC2 were associated with the metabolism of VCZ (Allegra et al., 2018). However, oral bioavailability of VCZ was 96% in adult patients while it was only 44.6% in children (Walldorf et al., 2018), so the effect of these transporter genetic polymorphisms on VCZ metabolism may be different in adult patients.