Current Drug Metabolism - Online First

Drug interactions necessitate careful consideration in clinical practice. It is imperative for clinicians and pharmacists to monitor drug exposure and the co-administration of medications promptly in order to avert adverse outcomes and achieve optimal efficacy.

The prevalence of oral lesions varies from 28% to 60% in the short term after renal transplantation. The clinical use of metronidazole in the treatment of anaerobic bacterial infections among solid organ transplant recipients has been complicated by the potentially significant and unpredictable drug-drug interactions.

We present an unexpected clinically significant drug-drug interaction between tacrolimus and metronidazole in the early period after renal transplantation and describe the potential mechanism and clinical characteristics of this drug-drug interaction through a literature review.

A 34-year-old female experienced a 65% increase in dose-normalized tacrolimus trough concentration after intravenous administration of metronidazole at 1000 mg/day for 8 days. When metronidazole was switched from intravenous to oral for 5 days, dose-normalized tacrolimus trough concentration was still increased by 52.4%. The magnitude of tacrolimus-metronidazole drug-drug interaction seems to be contingent upon the dose of metronidazole and the route of metronidazole administration. After cessation of metronidazole for one month, this drug-drug interaction, as assessed by weight-normalized tacrolimus dose, may still persist.

In the early period following renal transplantation, the long-term concomitant use of metronidazole is likely to elevate the trough concentration of tacrolimus. Gene screening for CYP3A5*3/*3 and ABCB1 3435C>T in recipients of solid organ transplants may support individualized tacrolimus prescribing and facilitate the mitigation of risks associated with drug-drug interactions.

The clearance of digoxin in obese patients with renal impairment is reduced, leading to elevated serum concentrations and increased risks of digoxin toxicity. However, the exact mechanism of such alterations in obese patients remains unclear. Previous studies have suggested that the organic anion transporting polypeptide 4c1 (Oatp4c1, Slco4c1) mediates the elimination of digoxin at the basal membrane of the proximal tubule (PT), indicating its potential role in the pharmacokinetic changes in obese patients. This study aims to investigate the effects of a high-fat diet HFD on digoxin pharmacokinetics and transporter expression in mouse models and further analyze its significance by detecting the expression of transporters in human renal tissue samples.

First, HFD-induced obese mouse model was established. Mice were intraperitoneally injected with digoxin, and 24-hour urine samples and blood samples at five time points were collected. Pharmacokinetic evaluation was performed using liquid chromatography-tandem mass spectrometry. Renal pathological changes and the expression of digoxin transporters (Oatp4c1 and P-glycoprotein (P-gp)) were assessed using histological staining, Western blots (WB), as well as quantitative polymerase chain reaction (qPCR). Human renal pathologic alterations and expression of transporter proteins showed consistency with the results of animal experiments. To explore the potential use of gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) as a marker for Oatp4c1 function, drug interactions between digoxin and Gd-EOB-DTPA were assessed in mice.

HFD-induced obese mice showed significant increases in body weight, blood glucose, and triglyceride, along with elevated blood concentration of digoxin, increased areas under the curve, reduced renal clearance rate (CLr), and prolonged half-life (t1/2). Histological staining revealed proximal tubular epithelial cell detachment and slight fibrosis in the kidney of the HFD group, with decreased expression of villin, the protein marker for PT. Immunofluorescent staining and Western blots for digoxin transporters showed a significant reduction of Oatp4c1 and P-gp proteins, suggesting that the renal elimination of digoxin was affected by the reduced level of Oatp4c1 and P-gp proteins. Co-administration of digoxin and Gd-EOB-DTPA resulted in a reduced clearance of Gd-EOB-DTPA, suggesting that both share the same transporter. The blood concentration of Gd-EOB-DTPA was higher (77.5%) in the HFD group. Renal magnetic resonance imaging (MRI) intensity was lower in the HFD group after Gd-EOB-DTPA administration compared to the Chow group.

Obesity-induced kidney damage results in decreased Oatp4c1 and P-gp expression and function in PT, resulting in a reduction of digoxin renal clearance. The inhibition of Gd-EOB-DTPA clearance by digoxin co-administration and the increased Gd-EOB-DTPA blood concentration in the HFD group both suggest its potential use in characterizing the Oatp4c1 function in vivo.

The female reproductive system is susceptible to oxidative stress, which can interfere with ovulation, menstrual cycles, egg quality, and tubal function, ultimately leading to infertility. Antioxidants might play a crucial role in protecting reproductive health by neutralizing Reactive Oxygen Species (ROS) and preventing cellular damage.

To provide an overview of the research that has been performed on the benefits of antioxidant supplementation for increasing female fertility.

We conducted a comprehensive search of PubMed, Embase, and Google for full-text, English-language publications between 2000 and 2023 that investigated the relationship between antioxidant supplementation and improvements in female fertility.

Antioxidants have been investigated for their potential to improve fertility outcomes in subfertile women. Antioxidant supplementation shows promise in mitigating these effects by neutralizing excess ROS and restoring balance, leading to improved egg count and fertility outcomes. However, it is important to note that the effectiveness of antioxidant supplementation can vary depending on individual health factors and the specific antioxidants used. Studies suggest that a combination of antioxidants, such as vitamins C and E, selenium, and coenzyme Q10, may be more beneficial than single supplements. Although individual research has shown beneficial correlations between different antioxidant supplementation and female fertility, study repeatability is poor. As a result, further large-scale, well-designed clinical trials are necessary to better understand the precise role and optimal combinations of antioxidants for enhancing fertility in subfertile women.

This review study offers crucial insights into the complex connection between OS and female reproductive health. It highlights the potential advantages of antioxidant supplements as a preventative strategy. To enhance female fertility outcomes, further research, particularly randomized controlled clinical trials, is needed to determine best practices, identify populations that could benefit the most, and explore innovative antioxidant treatments.

Di-2-ethylhexylphthalate (DEHP) is utilized as a plasticizer in polyvinylchloride products (PVC). When medical devices like blood bags, tubes, and syringes are employed, DEHP leaches out of the PVC polymers and enters biological fluids through non-covalent binding. The presence of DEHP in peripheral blood leads to contamination of bone marrow. Previous research has demonstrated that this chemical induces oxidative stress, which adversely affects the viability and osteo-differentiation of bone marrow mesenchymal stem cells (BMSCs). Hence, our current study aims to utilize gallic acid (GA), a natural antioxidant, to alleviate the inhibitory effects of DEHP on BMSCs' osteogenic differentiation.

In osteogenic media, BMSCs extracted from Wistar rats were treated with 0.25 μM of GA and 100 μM of DEHP individually and in combination for 20 days. Then viability, total protein, malondialdehyde (MDA), total antioxidant capacity (TAC), catalase (CAT) and superoxide dismutase (SOD), alkaline phosphatase activity, production of collagen1A1 protein as well as expression of Bmp2 and 7, Smad1, Runx2, Oc, Alp, Col-1a1 genes were investigated.

The viability and differentiation ability of BMSCs was significantly (p<0.0001) decreased by DEHP, while GA significantly (P<0.0001) ameliorated the effect of DEHP. DEHP caused a significant decrease (P<0.0001) in the total protein and collagen-1A1 concentration, TAC and activity of antioxidant enzymes, but significantly (P<0.001) increased MDA level. In addition, DEHP caused a significant decrease in the expression of osteo-related genes. In the co-treatment group, GA mitigated the toxic effects of DEHP compared to the control group by inhibiting DEHP-induced oxidative stress and enhancing cell viability and osteo-differentiation properties.

These results confirm that GA reduces the negative effects of DEHP on the osteo-differentiation of BMSCs at the cellular level. However, further studies are necessary to validate these findings.

Vincosamide, an indole alkaloid extracted from Nauclea officinalis, exhibits a range of pharmacological activities, such as anti-tumor, antibacterial, and anti-inflammatory properties. However, despite its promising therapeutic applications, there is a notable gap in research focused on the metabolic pathways of vincosamide.

This study aims to investigate the metabolism of vincosamide both in vitro and in vivo in rats, and to elucidate its metabolic pathways.

Samples of liver microsomal incubation, plasma, bile, urine, and feces following vincosamide administration were analyzed by ultra-high performance liquid chromatography-quadrupole-Exactive Orbitrap-high resolution mass spectrometry (UHPLC-Q-Exactive Orbitrap HRMS). The collected data were analyzed using Compound Discovery 3.2 software and the molecular network method. The metabolites identified through these methodologies were subsequently validated using Xcalibur 4.1 software, which provided information on retention times, parent ions, and characteristic fragment ions.

A total of 37 metabolites were identified, including 8 in vitro and 32 in vivo (3 in plasma, 7 in bile, 22 in urine, and 17 in feces). While the metabolism of vincosamide differs in vitro and in vivo in rats, the type of metabolic reaction that occurs is well-defined. The predominant metabolic pathways are oxidation, reduction, deglycosylation, hydration, glucuronidation, methylation, sulfation, glycine conjugation, cysteine conjugation, taurine conjugation, and complex reactions.

This study elucidates the metabolism of vincosamide in vitro and in vivo in rats, thereby expanding the metabolite profile of vincosamide. These findings provide a foundation for the potential development of new drugs based on vincosamide.

The use of computer-aided toxicity and Pharmacokinetic (PK) prediction studies are of significant interest to pharmaceutical industries as a complementary approach to traditional experimental methods in predicting potential drug candidates.

In the present study, in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of valeric acid were examined using SwissADME and ADMETlab web tools.

The drug-likeness prediction results revealed that valeric acid adheres to the Lipinski rule, Pfizer rule, and GlaxoSmithKline (GSK) rule. From a pharmacokinetic perspective, valeric acid is anticipated to have the best absorption profile including cell permeability and bioavailability. Plasma Protein Binding (PPB) and Blood–Brain Barrier (BBB) permeability may have a positive effect on Central Nervous System modulating (CNS). There is a minimal chance of it being a substrate for cytochrome P2D6 (CYP). Except for a “very slight risk” for eye corrosion and eye irritation, none of the well-known toxicities in valeric acid were anticipated, which was compatible with wet-lab data. The molecule possesses no environmental hazard as analyzed with common indicators such as bio-concentration factor and LC50 for fathead minnow and daphnia magna. The toxicity parameters identified valeric acid as nontoxic to androgen receptors, antioxidant response element, mitochondrial membrane receptor, heat shock element, and tumor suppressor protein (p53), except Peroxisome Proliferator-Activated Receptor- gamma (PPAR-γ) was found to be medium toxicity. However, no toxicophores were found out of seven parameters.

Overall, the ADMETLab evaluated that valeric acid has favorable pharmacokinetic and drug-likeness profiles, making it a promising drug candidate for new drug development.