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1.
Pharmaceutics ; 16(7)2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-39065631

RESUMEN

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson's disease. We developed an analytical method for 2-QBA using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49-97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3-83.7%. Secondary peaks were observed at approximately 4-8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the ß-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic-pharmacodynamic correlation of 2-QBA to assess its potential as a drug.

2.
Pharmaceutics ; 16(6)2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38931920

RESUMEN

Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse, and dog hepatocytes but moderately metabolized in rat and monkey hepatocytes when estimated from the metabolic stability of this compound in hepatocyte suspension and when 18 phase I metabolites and 5 phase II metabolites [i.e., N-dearylation (M6), hydroxylation (M1, M19, M21), dihydroxylation (M7, M8, M14, M22), trihydroxylation (M13, M18), hydroxylation and reduction (M20), dihydroxylation and reduction (M9, M16), hydrolysis (M23), hydroxylation and glucuronidation (M11, M15), hydroxylation and sulfation (M17), dihydroxylation and sulfation (M10, M12), N-dearylation and hydroxylation (M3, M4), N-dearylation and dihydroxylation (M5), and N-dearylation and trihydroxylation (M2)] were identified from JP-1366 incubation with the hepatocytes from humans, mice, rats, dogs, and monkeys. Based on the cytochrome P450 (CYP) screening test and immune-inhibition analysis with CYP antibodies, CYP3A4 and CYP3A5 played major roles in the metabolism of JP-1366 to M1, M3, M4, M6, M8, M9, M13, M14, M16, M18, M19, M21, and M22. CYP1A2, 2C8, 2C9, 2C19, and 2D6 played minor roles in the metabolism of JP-1366. UDP-glucuronosyltransferase (UGT) 2B7 and UGT2B17 were responsible for the glucuronidation of M1 to M15. However, JP-1366 and active metabolite M1 were not substrates for drug transporters such as organic cation transporter (OCT) 1/2, organic anion transporter (OAT) 1/3, organic anion transporting polypeptide (OATP)1B1/1B3, multidrug and toxic compound extrusion (MATE)1/2K, P-glycoprotein (P-gp), and breast cancer-resistant protein (BCRP). Only M1 showed substrate specificity for P-gp. The findings indicated that drug-metabolizing enzymes, particularly CYP3A4/3A5, may have a significant role in determining the pharmacokinetics of zastaprazan while drug transporters may only have a small impact on the absorption, distribution, and excretion of this compound.

3.
Carbohydr Polym ; 338: 122197, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38763711

RESUMEN

Transdermal rotigotine (RTG) therapy is prescribed to manage Parkinson's disease (Neupro® patch). However, its use is suffered from application site reactions. Herein, drug nanocrystalline suspension (NS)-loaded hydrogel (NS-HG) employing polysaccharides simultaneously as suspending agent and hydrogel matrix was constructed for transdermal delivery, with alleviated skin irritation. RTG-loaded NS-HG was prepared using a bead-milling technique, employing sodium carboxylmethyl cellulose (Na.CMC) as nano-suspending agent (molecular weight 90,000 g/mol) and hydrogel matrix (700,000 g/mol), respectively. NS-HG was embodied as follows: drug loading: ≤100 mg/mL; shape: rectangular crystalline; crystal size: <286.7 nm; zeta potential: -61 mV; viscosity: <2.16 Pa·s; and dissolution rate: >90 % within 15 min. Nuclear magnetic resonance analysis revealed that the anionic polymers bind to RTG nanocrystals via charge interaction, affording uniform dispersion in the matrix. Rodent transdermal absorption of RTG from NS-HG was comparable to that from microemulsions, and proportional to drug loading. Moreover, NS-HG was skin-friendly; erythema and epidermal swelling were absent after repeated application. Further, NS-HG was chemically stable; >95 % of the drug was preserved up to 4 weeks under long term (25 °C/RH60%), accelerated (40 °C/RH75%), and stress (50 °C) storage conditions. Therefore, this novel cellulose derivative-based nanoformulation presents a promising approach for effective transdermal RTG delivery with improved tolerability.


Asunto(s)
Administración Cutánea , Carboximetilcelulosa de Sodio , Hidrogeles , Nanopartículas , Piel , Tetrahidronaftalenos , Tiofenos , Tiofenos/química , Tiofenos/administración & dosificación , Animales , Hidrogeles/química , Nanopartículas/química , Carboximetilcelulosa de Sodio/química , Tetrahidronaftalenos/química , Tetrahidronaftalenos/administración & dosificación , Piel/efectos de los fármacos , Piel/metabolismo , Masculino , Absorción Cutánea/efectos de los fármacos , Ratas , Ratones , Portadores de Fármacos/química , Ratas Sprague-Dawley , Liberación de Fármacos
4.
J Anim Sci Technol ; 66(1): 103-114, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38618039

RESUMEN

This study was done to investigate the effects of the incorporation of Achyranthes japonica extracts (AJE) in diet on the production parameters of growing pigs. Exp 1: Total, 105 crossbred pigs (average body weight: 24.47 ± 2.46 kg) were used in a 6-week feeding trial. Pigs (seven replicates, five pigs per pen) were allotted randomly to three treatments. Dietary treatments: CON (basal diet); basal diet with 0.025% AJE, and basal diet + 0.050% AJE). Growth performance, nutrient digestibility, fecal microbial count, and fecal noxious gas were assessed in this study. Average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio (G:F) were not affected by the addition of up to 0.05% AJE. In the case of apparent total tract digestibility (ATTD), dry matter (DM), nitrogen (N), and digestible energy (DE) were not changed in 3rd and 6th weeks of the feeding trial through the addition of AJE up to 0.05% in the growing pig diet. In microbial count, Lactobacillus and Escherichia coli count at 3rd and 6th week was similar in all the treatment diets. The inclusion of AJE at levels up to 0.05% in growing pig diet had no effect on the production of NH3, H2S, acetic acid, and CO2 in the feces. After ending the Exp 1, a total of nine pigs were divided into three treatment groups. Treatment diets were included, TRT1, basal diet + powder quercetin 30 g; TRT2, basal diet + powder quercetin 150 g; TRT3, basal diet + powder quercetin 300g. Rate of absorption in blood was increased with the higher dose of quercetin. The results suggested incorporation of AJE up to 0.05% has no significant effect on ADG, ADFI, and G:F, as well as DM, N, and DE digestibility, fecal microbial count, and fecal noxious gas emission in growing pigs, even though no negative effect was found.

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