Extensive Metabolism Research Articles

Quality-by-Design-Driven Nanostructured Lipid Scaffold of Apixaban: Optimization, Characterization, and Pharmacokinetic Evaluation.

Apixaban, an anticoagulant, is limited in its efficacy due to poor solubility, low bioavailability, and extensive metabolism. This study investigates the application of nanostructured lipid carriers (NLCs) to enhance the bioavailability of Apixaban. NLCs were prepared using the high-pressure homogenization method. The influence of independent variables, viz., the amount of Tween 80, HPH pressure, and the number of HPH cycles, were studied using a 23 factorial design. The average particle size, PDI, zeta potential, and entrapment efficiency of the optimized NLCs were found to be 232 ± 23 nm, with 0.514 ± 0.13 PDI and zeta potential of about -21.9 ± 2.1 mV, respectively. Additionally, concerning the thermal and crystallographic properties of the drug, the NLCs showed drug entrapment without altering its potency. The in-vitro drug release studies revealed an immediate release pattern, followed by sustained release for up to 48 h. In-vivo pharmacokinetic experiments demonstrated that Apixaban-loaded NLCs exhibited higher values of t1/2 (27.76 ± 1.18 h), AUC0-∞ (19,568.7 ± 1067.6 ng·h/mL), and Cmax (585.3 ± 87.6 ng/mL) compared to free drugs, indicating improved bioavailability. Moreover, a decrease in the elimination rate constant (Kel) reflected the sustained effect of Apixaban with NLCs. NLCs offer improved oral absorption rates and enhanced therapeutic impact compared to free drugs, potentially reducing dose frequency and improving patient outcomes.

Intranasal delivery of doxepin: enhancing brain targeting efficiency utilizing nanostructured lipid carriers for a biopharmaceutics drug disposition classification system class-I drug

Doxepin, a Class-I Biopharmaceutics Drug Disposition Classification System (BDDCS) drug, exhibits poor bioavailability due to extensive first-pass metabolism. This research focuses on enhancing the delivery of doxepin by formulating nanostructured lipid carriers (NLCs) through the utilization of the Box–Behnken Design methodology. These optimized NLCs are intended for intranasal administration, with the ultimate goal of improving nose-to-brain drug delivery. NLCs were formulated using a high-speed homogenization technique. The optimized batch had a small particle size (75.80 ± 5.48 nm, PDI = 0.286), high entrapment efficiency (94.10 ± 0.16%), and sustained ex vivo release (82.25 ± 4.61% at 24 h). Characterization studies confirmed the conversion of doxepin from a crystalline to an amorphous state with uniform distribution in the lipid matrix. In vivo pharmacokinetic studies in rats showed significantly higher doxepin concentration in the brain tissue (Cmax = 16.77 µg/g, tmax = 30 min) after intranasal administration compared to intravenous administration (Cmax = 2.53 µg/g, tmax = 6 h). High-drug targeting efficiency (DTE = 284.3%) and direct transport percentage (DTP = 64.8%) suggested direct penetration of NLCs in the brain via olfactory and trigeminal pathways. In conclusion, the study highlights the potential of NLCs to improve the bioavailability of doxepin through nose-to-brain delivery and thereby potentially enable the treatment of neurological disorders.

The Diversity of CYP2C19 Polymorphisms in the Thai Population: Implications for Precision Medicine.

CYP2C19 plays a major role in the metabolism of various drugs. The most common genetic variants were the CYP2C19*2 and *3 alleles (rs4244285 and rs4986893, non-functional variants). In previous studies, we found that genetic polymorphisms in CYP2C19 variants influenced the active metabolites of clopidogrel and caused major adverse cardiovascular and cerebrovascular effects. However, the distribution of CYP2C19 varies among ethnic groups and according to adverse drug reactions. This study aimed to investigate the frequency of CYP2C19 genetic polymorphisms in the Thai population and analyze the differences in the frequency of CYP2C19 genetic polymorphisms between Thai and other populations. This study enrolled 211 unrelated healthy Thai individuals in total. We performed a real-time polymerase chain reaction to genotype CYP2C19*2 (681G > A) and CYP2C19*3 (636G > A). In the Thai population, the CYP2C19*1 allele was the most prevalent at 70.14%, while the CYP2C19*2 and *3 alleles were found at frequencies of 25.36% and 4.50%, respectively. Conversely, the CYP2C19*3 allele was not detected in Caucasian, Hispanic, African, Italian, Macedonian, Tanzanian, or North Indian populations. The phenotypic profile of this gene revealed that the frequency of intermediate metabolizers (IMs) is nearly equal to that of extensive metabolizers (EMs), at 42.65% and 48.82% respectively, with genotypes *1/*2 (36.02%) and *1/*3 (6.63%). Likewise, poor metabolizers (PMs) with genotypes *2/*2 (6.16%), *2/*3 (2.37%), and *3/*3 (<1%) are more prevalent in our population as well. The distribution of CYP2C19 genotype and phenotype influenced by non-functional alleles has potential as a pharmacogenomics biomarker for precision medicine and is dependent on an ethnic-specific genetic variation database.

Molecular docking, molecular dynamics simulation, preparation, and characterization of naltrexone-phospholipid complex: A novel cargo with improved loading into multivesicular liposomes

Naltrexone hydrochloride (NTX), a water-soluble opioid receptor antagonist, is prescribed widely for opioid and alcohol dependence and pain reduction. However, the significant limitations of NTX are low lipophilicity and extensive first-pass metabolism. This study aimed to design and prepare a novel phospholipid complex of NTX and load it into multivesicular liposomes (MVLs). In silico studies, including molecular docking and molecular dynamics (MD) simulation, were performed to determine the interactions between NTX and phospholipid and evaluate their best molar ratio to prepare the complex, respectively. The NTX phospholipid complex was prepared by solvent evaporation technique and characterized by PXRD, SEM, FTIR, 1HNMR, solubility study, and n-octanol/water partition coefficient analyses. NTX-SPC complex-loaded MVLs (NTX-SPC-MVLs) were prepared by the double-emulsion method and characterized by encapsulation efficiency (EE)%, size, PXRD, FTIR, SEM, and release pattern. MD simulation reported the 1:1.5 M ratio of NTX to phospholipid as the best molar ratio. Complexation led to reduced water solubility and enhanced n-octanol/water partition coefficient. Loading of NTX-SPC complex into MVLs enhanced EE and extended the release duration in comparison to NTX MVLs. Thus, the NTX-SPC complex may be an appropriate system to enhance the physicochemical features of NTX and improve the EE in vesicular drug delivery systems like MVLs.

Unveiling the Preparation and Characterization of Lercanidipine Hydrochloride in an Oral Solid Self-Nanoemulsion for Enhancing Oral Delivery.

Chronic kidney disease (CKD) is becoming increasingly prevalent worldwide, particularly among the elderly, along with an increase in the incidence of hypertension and cardiovascular disorders. Developing lipid-based oral dosage forms with a higher expected bioavailability of antihypertensive drugs with nephroprotective effects poses a challenge. Lercanidipine hydrochloride (LRCH) is a newer type of third-generation dihydropyridine calcium channel blocker that functions as an antihypertensive and has significant nephroprotective effects. Due to its extensive first-pass metabolism, its bioavailability is about 10% and increases to 3-4 times when taken with a high-fat meal. Targeting this drug to the lymphatic system using the solid self-nano-emulsifying drug delivery system (SSNEDDS) is a promising approach for improving LRCH's bioavailability and dispersion rate. SSNEDDS combines the benefits of both liquid self-emulsifying and solid dosage forms, improving drug stability and extending storage time. In this study, liquid SNEDDS composed of 10% peppermint oil, 67% Tween 20, and 22.5% propylene glycolwas solidified using two adsorbent agent mixtures (SSNEDDS1: Avicel PH 101 and Aerosil 200) and (SSNEDDS2: Avicel PH 102 and Aerosil 200) separately. The prepared formulations were evaluated for powder flow, drug content, and an in-vitro dispersion test in comparison to the brand-marketed tablet as a standard or pure drug. DSC and X-ray diffraction analysis were also used. The SSNEDDS2 shows excellent flowability, a higher drug content (99.761%), and a significantly higher and faster dispersion rate of 100% within 10 minutes compared to 92% of the marketed LRCH tablet and 18.1% of the pure drug for 60 minutes. The solid-state characterization of the formulation composed of SSNEDDS2 confirmed that the LRCH was in an amorphous form inside the solidified nano system without interacting with the excipient. This study successfully prepared LRCH using the promising strategy of SSNEDDS as a hard gelatin capsule with a higher dispersion rate. It improved its stability and expected bioavailability compared to the brand-marketed tablet as the standard.

The Influence of CYP2D6 Gene Variants on Tamoxifen Therapy in Breast Cancer Patients in the Asian Region

reast cancer is one of the most prevalent cancers in society, especially among women. Tamoxifen is often used as a first-line therapy for breast cancer and reduces the risk of recurrence in ER+ breast cancer. However, the response to treatment varies due to genetic variability resulting from polymorphisms in the DNA encoding drug-metabolism enzymes, including the CYP2D6 gene. This literature review aimed to evaluate the impact of CYP2D6 gene variants on the effectiveness of tamoxifen in breast cancer treatment. A literature search was conducted through PubMed, Google Scholar, and BMC Cancer using relevant keywords. The selected articles were no more than ten years old (2014-2024), with criteria for inclusion and exclusion. The review of articles from various research journals found that in the Asian region, the CYP2D6 gene variant allele *10 was most frequently seen, resulting in Intermediate Metabolism (IM) in tamoxifen therapy. Patients with IM metabolism tend to have suboptimal therapeutic responses and require tamoxifen dose adjustments.Conversely, patients with Normal Metabolism (NM/EM) tend to have better therapeutic responses. Genetic variability in the CYP2D6 gene affects the activity of the CYP2D6 enzyme, which functions to convert tamoxifen into its active form, Endoxifen. Some individuals may have low (Poor Metabolizer), Intermediate (Intermediate Metabolizer), Normal (Extensive Metabolizer), or even high (Ultra-rapid Metabolizer) enzyme activity. Therefore, adjusting tamoxifen therapy based on patient genetic information is essential for optimal treatment, especially in Asia, where the CYP2D6 gene variant allele *10 is most commonly found, resulting in IM metabolism

Hepatic injury and hepatic failure adverse events in 3,4-methylenedioxymethamphetamine users reported to the FDA Adverse Event Reporting System.

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.

In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1

In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species. The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively. The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat. Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.

Enhancing Oral Bioavailability of Simvastatin Using Uncoated and Polymer-Coated Solid Lipid Nanoparticles.

Simvastatin (SVA) is a well-prescribed drug for treating cardiovascular and hypercholesterolemia. Due to the extensive hepatic first-pass metabolism and poor solubility, its oral bioavailability is 5%. Solid lipid nanoparticles (SLNs) and hydrogel-coated SLNs were investigated to overcome the limited bioavailability of SVA. Four different lipids used alone or in combination with two stabilizers were employed to generate 13 SLNs. Two concentrations of chitosan (CS) and alginate (AL) were coating materials. SLNs were studied for particle size, zeta potential, in vitro release, rheology, and bioavailability. The viscosities of both the bare and coated SLNs exhibited shear-thinning behavior. The viscosity of F11 (Chitosan 1%) at 20 and 40 rpm were 424 and 168 cp, respectively. F11 had a particle size of 260.1 ± 3.72 nm with a higher release; the particle size of F11-CS at 1% was 524.3 ± 80.31 nm. In vivo studies illustrated that F11 had the highest plasma concentration when compared with the SVA suspension and coated chitosan (F11 (Chitosan 1%)). Greater bioavailability is measured as (AUC0→24), as compared to uncoated ones. The AUC for F11, F11-CS 1%, and the SVA suspension were 1880.4, 3562.18, and 272 ng·h/mL, respectively. Both bare and coated SLNs exhibited a significantly higher relative bioavailability when compared to that from the control SVA.

Impact of CYP2D6 polymorphisms on adverse events in patients with breast cancer treated with tamoxifen: Insights from an early dose escalation trial in CYP2D6 poor metabolizers.

547 Background: Tamoxifen is widely used in treating hormone receptor-positive breast cancer. It is primarily metabolized by the CYP2D6 enzyme to yield active metabolites. However, CYP2D6 polymorphisms have been associated with a differential response to tamoxifen. In a clinical trial involving an early dose escalation of tamoxifen in poor metabolizers, we found endoxifen concentration levels similar to those of patients with extensive phenotype, and no long-term survival differences among CYP2D6 phenotypes. However, the impact of that dose escalation on side effect incidence was not addressed. Methods: In this study, we analyzed the incidence of specific side effects - osteoarticular pain, hot flashes, asthenia, and uterine alterations - in 86 breast cancer patients, differentiated by their CYP2D6 phenotype estimated according to the Clinical Pharmacogenetics Implementation Consortium. In poor metabolizers, the tamoxifen standard dose of 20 mg/day was escalated to 40 mg/day and 60 mg/day for 4 months each, and then treated with 20 mg/day until completing the treatment. Kaplan-Meier analysis and Cox proportional hazards regression model were employed to assess the relationship between the CYP2D6 phenotype and the incidence of these side effects. Results: The median follow-up time was 139.5 months. The analyses revealed that only uterine changes showed significant differences between CYP2D6 phenotypes, with a lower incidence in extensive metabolizers (P-value &lt; 0.001 in Kaplan-Meier; HR in Cox of 0.195, 95% CI 0.073 - 0.521, P = 0.001). This finding persisted after adjustment for the covariates tumor grade, size, nodal status, chemotherapy, and radiotherapy in multivariate Cox regression (HR 0.098, 95% CI 0.020 - 0.466, P = 0.004). Selection of a subgroup through Propensity Score Matching (21 vs 21) corroborated these results. The spectrum of uterine changes and pathologies included endometrial hyperplasia, polyps, adenocarcinoma, myometrial or endometrial thickening, and the presence of multiple myomas. Conclusions: Our study indicates that an early increase in tamoxifen dose in poor metabolizer patients according to CYP2D6 polymorphisms may significantly affect the incidence of uterine changes, but not the incidence of osteoarticular pain, hot flashes, or asthenia. Clinical trial information: 2007-002942-40/ES .

Pharmacogenomics in primary care: a quality improvement project at Alconbury and Brampton surgeries 2019-2023.

Treatment of depression is common in primary care but not every antidepressant is effective in every patient. Adverse drug reactions are common, imposing a substantial burden on the patient and the NHS. Pharmacogenomics (PGx) utilises an individual's genetic makeup to predict their response to medications. By tailoring prescriptions to a person's genetic profile, PGx can significantly reduce adverse drug reactions, identify non-responders to medications, and enhance overall patient outcomes. To see if PGx testing for antidepressants can be undertaken in general practice as part of 'usual care'; to increase GP and patient awareness of PGx testing; to alter patient treatment according to the results of testing; and to sustain these changes at 4 years. In 2019, 23 patients were recruited by GPs at the surgery. They consented and had cheek swabs to check their genetic profile to common antidepressants. Results were reviewed at 1 week by the GP and patient, treatment changes made and reviewed again at 4 years. On the CYP2D pathway, 19/23 patients were extensive (normal) metabolisers, one intermediate and two poor. These two had their treatments changed. At 4-year review 19/23 were on appropriate treatment (two had been stopped) but two had inappropriate drug treatment. On CYP2C19 pathway, 10/23 were normal metabolisers, eight intermediate, zero poor but five ultrarapid (they had their treatment changed). At 4-year review, 20/23 were on appropriate treatment (two stopped) and one inappropriate. PGx testing works in primary care, improving patient outcomes sustainably.

A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (<0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis

Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype onparoxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P=0.03 and P=0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

The impact of CYP2C19 genotypes on steady-state plasma concentration of escitalopram in South Indian population with Major Depressive Disorder

Background: Among depressed patients, escitalopram plasma levels differed between those who were considered as extensive metabolizers and poor metabolizers of CYP2C19. However, the majority of research utilized the dose-response relationship. Consequently, we investigated the effect of variations in the CYP2C19 gene on the levels of drug in the bloodstream of individuals suffering from Major Depressive Disorder (MDD) in south India. Methods: A total of 109 individuals with MDD who were prescribed escitalopram at doses of 5, 10, 15, or 20 mg daily participated in this research. We used HPLC with SPD-10AVP UV-Visible detector to measure the escitalopram concentrations in the blood. The polymorphisms of the CYP2C19 were determined by employing the PCR techniques. Results: Our study found that 55% of the subjects were intermediate metabolizers, followed by extensive (19.3%), poor (17.4%), and ultra-rapid (8.3%). The significant correlation is identified between the steady state plasma concentration and Sex with (P - Value &amp;lt; 0.05), insignificant correlation was seen in Age and BMI with (P - Value &amp;gt; 0.05). The majority of gene variants seen in the study population were CYP2C19*1/*2, accounting for 49 individuals (44.9%). Conclusion: These findings showed that sex had a substantial impact on the CYP2C19 genetic variation. Medication administration to individuals with CYP2C19PM requires special caution.

Integrating Clopidogrel's First-Pass Effect in a Joint Semi-Physiological Population Pharmacokinetic Model of the Drug and Its Inactive Carboxylic Acid Metabolite.

Clopidogrel (CLO), a pro-drug for preventing thrombotic events, undergoes rapid absorption and extensive metabolism, with approximately 85-90% converted to an inactive carboxylic acid metabolite (CLO-CA) and the remaining to an active thiol (CLO-TH). Few pharmacokinetic models for the drug and its metabolites exist, with most focusing on CLO-TH. Although CLO-CA is inactive, its predominant (compared to its parent drug and metabolites) presence in plasma underscores the importance of characterizing its formation and pharmacokinetic profile. This study aimed to characterize the process of the absorption of CLO and its conversion to CLO-CA via developing a population pharmacokinetic model. Individual participants' data from two bioequivalence studies were utilized. Extensive blood samples were collected at predetermined intervals, including 841 concentrations of CLO and 1149 of CLO-CA. A nonlinear, mixed-effects modelling approach using NONMEM® software (v 7.5) was applied. A one-compartment model was chosen for CLO, while a two-compartment proved optimal for CLO-CA. Absorption from the depot compartment was modeled via two transit compartments, incorporating transit rate constants (Ktr). A semi-physiological model explained the first-pass effect of CLO, integrating a liver compartment. The estimated mean transit times (MTTs) for the studies were 0.470 and 0.410 h, respectively. The relative bioavailability for each study's generic medicine compared to the reference were 1.08 and 0.960, respectively. Based on the estimated parameters, the fractions metabolized to inactive metabolites (FiaM_st1 and FiaM_st2) were determined to be 87.27% and 86.87% for the two studies, respectively. The appropriateness of the final model was confirmed. Our model offers a robust framework for elucidating the pharmacokinetic profiles of CLO and CLO-CA.

Metabolic profiling of lumateperone in vitro and in vivo by UPLC-Q Exactive Orbitrap HRMS, and its pharmacokinetic study in rat plasma by LC-MS/MS

Lumateperone is a novel agent approved by FDA for treatment of schizophrenia in adults. To elucidate the species differences in the of biotransformation of lumateperone and its pharmacokinetic (PK) characteristics in rats, the metabolite identification of lumateperone was carried out in rat, dog and human liver microsomes, and rat plasma after oral administration using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry HRMS. Furtherly, the PK characteristics of lumateperone and its N-demethylated metabolite (M3) in rat plasma were investigated using a validated LC-MS/MS method following intravenous and oral administration. Fourteen phase I metabolites were found in liver microsomes and ten of them were observed in rat plasma. N-demethylation, carbonylation, dehydrogenation, and piperazine ring cleavage were main metabolic pathway of lumateperone. No unique metabolites were formed in human liver microsomes. After rapid absorption in rats, lumateperone was quickly metabolized and eliminated with bioavailability of less than 5%. The exposure level of M3 was about 1.5-fold higher than that of lumateperone in rat plasma. Lumatperone underwent extensive metabolism and was absorbed rapidly in rats. Metabolite M3 had equivalent or slightly higher exposure levels than lumateperone. This study provides essential PK information to facilitate further pharmacodynamic researches of lumateperone.

Brain-targeted nasal chrysin microemulsion for reducing oxidative stress in Parkinson's disease: Pharmacodynamic, biochemical evaluation and brain distribution studies

Chrysin, a flavone reported to treat Parkinson's, has limited oral bioavailability due to poor solubility and extensive pre-systemic metabolism. Therefore, a chrysin microemulsion (Chy-ME) was developed to improve bioavailability and brain targeting for treating Parkinson's disease via the nasal route. Chy-ME was prepared using the phase titration method and characterized for physicochemical parameters, nasociliotoxicity, and anti-Parkinson activities in a rotenone-induced experimental rat model. Chy-ME showed spherical globules with a size of 365.03 nm ± 6.8, a PDI of 0.107 ± 0.0316 and a zeta potential of −24.86 mV ± 2.286. It was non-irritant to the nasal mucosa and had in vitro and ex vivo drug release of 90.52 % and 68.67 %, respectively at 24 h. The in vivo study showed significantly improved locomotor activity and catalepsy score in the Chy-ME treated group than in oral or nasal chrysin suspension groups in rats. Chy-ME treatment showed elevated dopamine levels than the other two groups. Also, enhanced oxidative stress markers, i.e., SOD, GSH, and catalase levels, indicated the antioxidant potential of Chy-ME linked with preventing neuronal damage in Parkinson's. The maximum chrysin amount was estimated in the Chy-ME group (8.3212 ± 1.8125 μg/mL) than in oral (4.1364 ± 1.1095 μg/mL) or nasal (5.0879 ± 0.0058 μg/mL) suspension groups in the brain distribution study. In vivo studies revealed the brain-targeting potential of Chy-ME, evidenced by a substantial alleviation of Parkinson's symptoms, increased dopamine levels, improved oxidative stress markers and higher chrysin content in the brain. Therefore, nasal delivery of chrysin could overcome poor oral bioavailability and be explored for treating Parkinson-related symptoms as a brain-targeted approach.

In Vitro Stability and Pharmacokinetic Study of Pedunculoside and Its Beta-CD Polymer Inclusion Complex.

Pedunculoside, a triterpene saponin derived from various Ilex species, holds potential as a treatment for cardiovascular diseases. However, its clinical application is hindered by poor bioavailability, rapid elimination, and extensive intestinal metabolism to rotundic acid. To address these issues, a water-soluble inclusion complex of pedunculoside, namely, the beta-CD polymer inclusion complex of pedunculoside (pedunculoside-βCDP), was prepared in this study, and a comparative in vitro stability and pharmacokinetic behavior study was performed between pedunculoside and pedunculoside-βCDP. Both pedunculoside and pedunculoside-βCDP exhibited the highest stability in simulated gastric fluid and simulated intestinal fluid but were readily metabolized when co-incubated with Bifidobacterium adolescentis and Bifidobacterium breve. An LC-MS/MS analytical method for the simultaneous determination of pedunculoside and rotundic acid in rat plasma was successfully established, validated, and applied to investigate the pharmacokinetic behavior after rats were intravenously administered with pedunculoside or pedunculoside-βCDP. The results indicated that pedunculoside-βCDP could significantly improve the pharmacokinetic profile of pedunculoside by increasing plasma exposure, retarding elimination, and reducing intestinal metabolism. This study enhances our understanding of pedunculoside-βCDP's metabolic fate and pharmacokinetic properties and potentially advances its further research, development, and clinical application.

Fabrication and characterisation of nabumetone transferosomal gel for effective topical delivery

Nabumetone is a lipophilic drug with a log P value of 3.2 and belongs to BCS class II due to its poor water solubility. When administered orally, it undergoes extensive first-pass metabolism, shows low bioavailability, and has unfavourable side effects that cause discomfort. Topical route has gain importance by delivering therapeutic agents via this route due to its safety and convenience of drug administration and as of there are no any gel formulations available for it. The present investigation aimed to prepare, optimise, and characterise Nabumetone-loaded transferosomes (Nb-TF) using 32 factorial designs. Transferosomes were prepared by the thin-film hydration method. The optimised formulation was incorporated into gel form (Nb-TG) and evaluated for its mechanical characteristics, in-vitro release, ex-vivo permeation, skin irritancy test, anti-inflammatory activity, and stability studies. The Nb-TF 5 transferosomal formulation was optimised based on vesicle size and entrapment efficiency and incorporated into the gel base. Both normal (Nb-gel) and transferosome-loaded (Nb-TG) gel pH was within the range of topical skin pH. The viscosities of Nb-gel and Nb-TG were 1262 ± 54 cP and 1327 ± 12 cP, respectively. The drug content of both gels was found to be 96.31 ± 1.16 and 97.18 ± 0.94, respectively. Nb-TG showed higher diffusion and drug permeation than Nb-gel. The skin irritancy test indicates that there was no sign of any edema or erythema observed. Nb-TG showed a curative and preventive anti-inflammatory effect. Gels were found stable at both refrigerator and room temperature. Nb-TFs were proven to be potential carriers for transdermal controlled delivery of Nabumetone as it has deep penetration in the dermis layer which directly goes into the systemic circulation, enhances the bioavailability and reduced toxicities.