Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood–Brain Barrier

Shan, Yuheng; Cen, Yuying; Zhang, Yan‐Jin; Tan, Ruishu; Zhao, Jinping; Nie, Zhou; Zhang, Jiatang; Yu, Shengyuan

doi:10.1007/s11064-021-03472-1

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…Similarly, for cefovecin, several other cephalosporins are competitive inhibitors of human P-glycoprotein (Gosland et al, 1989;Shan et al, 2022). Thus, acquired P-glycoprotein deficiency may have contributed to eprinomectin-induced neurological toxicosis in four of six ABCB1 wildtype cats.…”

Section: Abcb1 Genotypementioning

confidence: 99%

“…Oxytetracycline, a structural analog of doxycycline, is a bovine P‐glycoprotein substrate (Schrickx & Fink‐Gremmels, 2007) suggesting doxycycline may be as well. Similarly, for cefovecin, several other cephalosporins are competitive inhibitors of human P‐glycoprotein (Gosland et al., 1989; Shan et al., 2022). Thus, acquired P‐glycoprotein deficiency may have contributed to eprinomectin‐induced neurological toxicosis in four of six ABCB 1 wildtype cats.…”

Section: Abcb1 Genotype Outcome Other Factorsmentioning

confidence: 99%

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Application of eprinomectin‐containing parasiticides at label doses causes neurological toxicosis in cats homozygous for ABCB11930_1931del TC

Mealey,

Burke,

Villarino

et al. 2024

Vet Pharm & Therapeutics

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The feline MDR1 mutation (ABCB11930_1931delTC) has been associated with neurological toxicosis after topical application of eprinomectin products labeled for feline use. Information was collected from veterinarians who submitted samples for ABCB11930_1931delTC genotyping. In most cases, the submission form indicated an adverse event involving eprinomectin, in other cases submitting veterinarians were contacted to determine whether the patient had experienced an adverse drug event involving eprinomectin. If so, additional information was obtained to determine whether the case met inclusion criteria. 14 cases were highly consistent with eprinomectin toxicosis. Eight cats were homozygous for ABCB11930_1931del TC (3 died; 5 recovered). Six cats were homozygous wildtype (2 died; 4 recovered). The observed ABCB11930_1931delTC frequency (57%) was higher than the expected frequency (≤1%) in the feline population (Fisher Exact test, p < .0001). Among wildtype cats, four were concurrently treated with potential competitive inhibitors of P‐glycoprotein. Results indicate that topical eprinomectin products, should be avoided in cats homozygous for ABCB11930_1931delTC. This is a serious, preventable adverse event occurring in an identifiable subpopulation treated with FDA‐approved products in accordance with label directions. Acquired P‐glycoprotein deficiency resulting from drug interactions may enhance susceptibility to eprinomectin‐induced neurological toxicosis in any cat, regardless of ABCB1 genotype.

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Section: Abcb1 Genotypementioning

confidence: 99%

Section: Abcb1 Genotype Outcome Other Factorsmentioning

confidence: 99%

Application of eprinomectin‐containing parasiticides at label doses causes neurological toxicosis in cats homozygous for ABCB11930_1931del TC

Mealey,

Burke,

Villarino

et al. 2024

Vet Pharm & Therapeutics

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“…The P-gp transporter has been shown to efflux a diverse range of molecules with varying chemical structures (cyclic, polar, nonpolar, linear, aromatic, linear-lipophilic) and molecular weights (250-4000 Da) (Table 1). Among the first P-gp competitive inhibitors discovered were cyclosporine-A and verapamil [77,78]. In a recent high-throughput screen of 10,804 compounds, Lee et al discovered 90 substrates, 55 of which were novel.…”

Section: Substrates Of P-gp and Its Drug Interactionmentioning

confidence: 99%

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Karthika

Sureshkumar

Zehravi

et al. 2022

Life

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P-glycoprotein (P-gp) is a major factor in the multidrug resistance phenotype in cancer cells. P-gp is a protein that regulates the ATP-dependent efflux of a wide range of anticancer medicines and confers resistance. Due to its wide specificity, several attempts have been made to block the action of P-gp to restore the efficacy of anticancer drugs. The major goal has been to create molecules that either compete with anticancer medicines for transport or function as a direct P-gp inhibitor. Despite significant in vitro success, there are presently no drugs available in the clinic that can “block” P-gp–mediated resistance. Toxicity, unfavourable pharmacological interactions, and a variety of pharmacokinetic difficulties might all be the reason for the failure. On the other hand, P-gp has a significant effect in the body. It protects the vital organs from the entry of foreign bodies and other toxic chemicals. Hence, the inhibitors of P-gp should not hinder its action in the normal cells. To develop an effective inhibitor of P-gp, thorough background knowledge is needed in this field. The main aim of this review article was to set forth the merits and demerits of the action of P-gp on cancer cells as well as on normal cells. The influence of P-gp on cancer drug delivery and the contribution of P-gp to activating drug resistance were also mentioned.

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“…P-gp is an efflux transporter encoded by the ABCB1 gene, and it is located in endothelial cells of the blood brain barrier (BBB). CEF is a substrate for P-gp and P-gp inhibitors such as cyclosporin A and verapamil may enhance the brain concentration of CFF ( Shan et al, 2022 ). Drugs of abuse also affect P-gp expression.…”

Section: Factors Related To the Efficacy Of Ceftriaxone In Preclinica...mentioning

confidence: 99%

Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation

Abulseoud

Alasmari²,

Hussein³

et al. 2022

Front. Neurosci.

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Dysregulation of glutamate homeostasis is a well-established core feature of neuropsychiatric disorders. Extracellular glutamate concentration is regulated by glutamate transporter 1 (GLT-1). The discovery of a beta-lactam antibiotic, ceftriaxone (CEF), as a safe compound with unique ability to upregulate GLT-1 sparked the interest in testing its efficacy as a novel therapeutic agent in animal models of neuropsychiatric disorders with hyperglutamatergic states. Indeed, more than 100 preclinical studies have shown the efficacy of CEF in attenuating the behavioral manifestations of various hyperglutamatergic brain disorders such as ischemic stroke, amyotrophic lateral sclerosis (ALS), seizure, Huntington’s disease, and various aspects of drug use disorders. However, despite rich and promising preclinical data, only one large-scale clinical trial testing the efficacy of CEF in patients with ALS is reported. Unfortunately, in that study, there was no significant difference in survival between placebo- and CEF-treated patients. In this review, we discussed the translational potential of preclinical efficacy of CEF based on four different parameters: (1) initiation of CEF treatment in relation to induction of the hyperglutamatergic state, (2) onset of response in preclinical models in relation to onset of GLT-1 upregulation, (3) mechanisms of action of CEF on GLT-1 expression and function, and (4) non-GLT-1-mediated mechanisms for CEF. Our detailed review of the literature brings new insights into underlying molecular mechanisms correlating the preclinical efficacy of CEF. We concluded here that CEF may be clinically effective in selected cases in acute and transient hyperglutamatergic states such as early drug withdrawal conditions.

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Effect of P-glycoprotein Inhibition on the Penetration of Ceftriaxone Across the Blood–Brain Barrier

Cited by 8 publications

References 41 publications

Application of eprinomectin‐containing parasiticides at label doses causes neurological toxicosis in cats homozygous for ABCB11930_1931del TC

Application of eprinomectin‐containing parasiticides at label doses causes neurological toxicosis in cats homozygous for ABCB11930_1931del TC

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Ceftriaxone as a Novel Therapeutic Agent for Hyperglutamatergic States: Bridging the Gap Between Preclinical Results and Clinical Translation

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