A safety signal for congenital strabismus associated with valproic acid: A pharmacovigilance analysis utilizing the FDA Adverse Event Reporting System database.

This pharmacovigilance study investigated the relationship between antiepileptic drugs and congenital strabismus, utilizing the FDA Adverse Event Report System database between 2014 and 2023. Out of 28 347 889 reports of adverse events in 10 937 764 cases, we identified 1104 reports of strabismus and 67 of congenital strabismus. Valproic acid was the most frequently implicated primary suspect drug (95 and 14 cases, respectively).

Relationship Between Clozapine and Non-Hematological Malignant Tumors: A Pharmacovigilance Analysis Using the FDA Adverse Event Reporting System Database.

Background And Objectives: Clozapine shows higher efficacy against treatment-resistant schizophrenia than other antipsychotics. This study aimed to investigate whether clozapine is associated with the risk of non-hematological malignant tumors, utilizing the US Food and Drug Administration (FDA) Adverse Event Report System (FAERS) database.

Methods: The records from the first quarter of 2004 to the third quarter of 2012 were used for disproportionality analysis, and patients who developed non-hematological malignant tumors were identified by the Standardized Medical Dictionary for Regulatory Activities Queries (SMQ).

Data Mining for Risks of Clozapine Side Effects, Including Neutropenia, Associated with Lithium Carbonate Administration: Analysis Using the Japanese Adverse Drug Event Report Database.

Background And Objective: Clozapine use is associated with development of neutropenia, and lithium carbonate may be co-administered to reduce this risk; however, this has not yet been adequately investigated. The present study examined whether lithium administration is associated with the risks of clozapine side effects, including neutropenia.

Methods: Data on patients taking clozapine, extracted from the Japanese Adverse Drug Event Report (JADER) database, were analyzed.

Relationship between lithium carbonate and the risk of Parkinson-like events in patients with bipolar disorders: A multivariate analysis using the Japanese adverse drug event report database.

The present study attempted to identify risk factors for Parkinson-like events using the Japanese adverse drug event report database. A total of 3521 patients with bipolar disorders were extracted from the database, and Parkinson-like events were detected in 111 (3.15%) using the standardized Medical Dictionary for Regulatory Activities queries.

Surveillance of drug overdose and identification of its risk factors by a multivariate analysis using the Japanese Adverse Drug Event Report database.

Background: Limited information is currently available on drug overdose in Japan. Therefore, the present study examined drug overdose using the Japanese Adverse Drug Event Report (JADER) database.

Methods: The records of drug overdose in patients were extracted from the JADER database.

Effect of Experimental Fanconi Syndrome on Tubular Reabsorption of Lithium in Rats.

Lithium, administered to patients of bipolar disorders, is mainly excreted into urine, and tubular reabsorption at the proximal tubule is involved in the renal handling of lithium. In this study, we examined the renal excretion of lithium in rats with Fanconi syndrome, characterized by defects of transports of various compounds at the proximal tubules, induced by maleic acid. After maleic acid was intravenously injected, mannitol and lithium chloride were infused in turn.

Citrus auraptene induces drug efflux transporter P-glycoprotein expression in human intestinal cells.

P-glycoprotein (encoded by MDR1) is a membrane transport protein expressed in the intestine, liver, kidney, placenta, and blood-brain barrier. It excludes various clinically important drugs from cells, such as verapamil, digoxin, tacrolimus, and vinblastine. Therefore, human P-glycoprotein plays important roles in drug absorption, distribution, and excretion.

Investigation of Fluorescent Substrates and Substrate-Dependent Interactions of a Drug Transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1).

Purpose: In this study, we investigated organic anion transporting polypeptide 2B1 (OATP2B1)-mediated uptake of fluorescent anions to better identify fluorescent substrates for in vitro OATP2B1 assays. The OATP2B1 is involved in the intestinal absorption and one of the pharmacokinetic determinants of orally administered drugs.

Methods: A microplate reader was used to determine the cellular accumulation of the fluorescent compounds into the OATP2B1 or the empty vector-transfected HEK293 cells.

Microtubule-targeting anticancer drug eribulin induces drug efflux transporter P-glycoprotein.

This study examined the effects of microtubule-targeting anticancer drugs (paclitaxel, cabazitaxel, and eribulin) on the expression of drug efflux transporter P-glycoprotein, which is encoded by . Paclitaxel and eribulin induced promoter activity in a concentration-dependent manner, while cabazitaxel had little effect in human intestinal epithelial LS174T cells. Overexpression of the nuclear receptor pregnane X receptor (PXR) gene () enhanced paclitaxel- and eribulin-induced activation, but expression of the nuclear receptor co-repressor silencing mediator for retinoid and thyroid receptors (SMRT) gene () repressed activation.

Enantioselective Drug Recognition by Drug Transporters.

Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect.

Effect of renal ischemia on urinary excretion of lithium in rats.

Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60 min or 90 min. After intravenous injection of lithium chloride at 25 mg/kg, the pharmacokinetic parameters of lithium were determined.

Effects of Natural Polyphenols on the Expression of Drug Efflux Transporter P-Glycoprotein in Human Intestinal Cells.

The drug efflux transporter P-glycoprotein, which is encoded by (), plays important roles in drug absorption, distribution, and elimination. We previously reported that dietary polyphenols such as quercetin, curcumin, honokiol, magnolol, caffeic acid phenetyl ester (CAPE), xanthohumol, and anacardic acid inhibit P-glycoprotein-mediated drug transport. In the present study, we investigated the effects of polyphenols on the expression of P-glycoprotein using human intestinal epithelial LS174T cells and a reporter plasmid expressing 10.

Nonlinear disposition of lithium in rats and saturation of its tubular reabsorption by the sodium-phosphate cotransporter as a cause.

We previously reported the contribution of sodium-phosphate cotransporter to the tubular reabsorption of lithium in rats. In the present study, the dose dependency of the renal handling of lithium was examined in rats. When lithium chloride at 1.

D-Malate decreases renal content of α-ketoglutarate, a driving force of organic anion transporters OAT1 and OAT3, resulting in inhibited tubular secretion of phenolsulfonphthalein, in rats.

d-Malate inhibits a Krebs cycle enzyme and the tubular transport of α-ketoglutarate, an intermediate of the Krebs cycle and the driving force for rat organic anion transporter 1 (rOAT1) and rOAT3 in the kidney. This study examined the effects of d-malate on the rat organic anion transport system. The uptake of 6-carboxyfluorescein by HEK293 cells expressing rOAT1 or rOAT3 was not affected by d-malate and l-malate.

Effects of phenylpropanoids on human organic anion transporters hOAT1 and hOAT3.

Human organic anion transporters hOAT1/SLC22A6 and hOAT3/SLC22A8 are highly expressed on the basolateral membrane of renal proximal tubules and mediate tubular uptake of anionic drugs from blood. They play an important role for drug disposition, and therefore close studies of their ligand recognition are important for drug therapy and development. In this study, we performed uptake experiments using HEK293 and fluorescent anion 6-carboxyfluorescein to asses the effects of phenylpropanoids on hOAT1 and hOAT3.

Enantioselective Effect of Flurbiprofen on Lithium Disposition in Rats.

Aims: Lithium is administered for treating bipolar disorders and is mainly excreted into urine. Nonsteroidal anti-inflammatory drugs inhibit this process. In this study, we examined the enantioselective effect of flurbiprofen on the disposition of lithium in rats.

Foscarnet, an inhibitor of the sodium-phosphate cotransporter NaPi-IIa, inhibits phosphorylation of glycogen synthase kinase-3β by lithium in the rat kidney cortex.

Lithium, which is used in the treatment of and prophylaxis for bipolar disease, inhibits glycogen synthase kinase-3β (GSK3β) by producing its phosphorylated form (p-GSK3β). GSK3β plays a role in apoptosis and some kinds of acute kidney injuries, and the formation of p-GSK3β is considered to contribute to protection against acute kidney injury. We previously reported that the sodium-phosphate cotransporter NaPi-IIa (SLC34A1) mediated the reabsorption of lithium in the rat kidney.

Lithium Interferes with the Urinary Excretion of Phenolsulfonphthalein in Rats: Involvement of a Reduced Content of α-Ketoglutarate, the Driving Force for Organic Anion Transporters OAT1 and OAT3, in the Kidney Cortex.

Aims: Lithium is effective in the treatment for bipolar disorder and is known to influence renal functions. The purpose of this study was to examine the effects of lithium on the renal organic anion transport system.

Methods: Pharmacokinetic experiments using rats and Western blotting were conducted.

Effects of Antiviral Drugs on Organic Anion Transport in Human Placental BeWo Cells.

Placental drug transfer is important for achieving better pharmacotherapy in pregnant women and in fetuses. In the present study, we examined the effects of anti-hepatitis C virus (HCV) and anti-HIV drugs on organic anion transport in human placental BeWo cells. The cellular uptake of two fluorescence organic anions, 8-(2-[fluoresceinyl]aminoethylthio)adenosine-3',5'-cyclic monophosphate (8-FcAMP) and fluorescein, was temperature and concentration dependent.

Minor contribution of biliary excretion in lithium elimination in rats.

Background: Lithium, which is often used for the treatment of bipolar disorders, is mainly recovered into urine after being orally administered. Due to the fact that it is completely absorbed via the gastrointestinal tract, it remains unknown whether biliary excretion is involved in the lithium disposition. In this study, we examined biliary excretion of lithium in rats and compared these with renal excretion.

Effects of natural nuclear factor-kappa B inhibitors on anticancer drug efflux transporter human P-glycoprotein.

Drug efflux transporter P-glycoprotein plays an important role in cancer chemotherapy. The nuclear factor-κB (NF-κB) transcription factors play critical roles in development and progression of cancer. In this study, the effects of natural compounds that can inhibit NF-κB activation on the function of P-glycoprotein were investigated using human MDR1 gene-transfected KB/MDR1 cells.

Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney.

Lithium, used for the treatment of bipolar disorders, is reabsorbed via sodium-transport system in the proximal tubule. This step causes intra-/inter-individual difference of lithium disposition, and it has not been unclear which transporter contributes. In this study, we examined effect of foscarnet and parathyroid hormone (PTH), inactivators for sodium-phosphate cotransporter, and phlorizin, a typical inhibitor for sodium-glucose cotransporter, on the disposition of lithium in rats.

Diuresis by intravenous administration of xanthurenic acid in rats, and inhibition by probenecid.

The conjugates with sulfate and glucoside of xanthurenic acid, a tryptophan metabolite, were reported to show natriuresis. Sulfotransferase for xanthurenic acid works in the renal proximal tubule to produce the sulfate of xanthurenic acid as well as the liver, and we recently found that xanthurenic acid is a substrate of renal organic anion transporter OAT1. The purpose of this study was to examine relationship between the transport by OAT1 and diuresis related with xanthurenic acid.