The pharmacokinetics of tolfenamic acid in Himalayan Griffon vultures. A better understanding for the safety of the drug in old world vultures.

Quantitative prediction of human pharmacokinetic drug-drug interactions and drug clearance using humanized liver chimeric mice: a review.

Impact of environmentally induced hypothermia on fentanyl and norfentanyl pharmacokinetics following intravenous administration to Wistar rats.

Nanotechnology has been applied to the diagnostic and therapeutic treatment of cancer, with Carbon Nanotubes (CNTs) serving as an effective platform for these processes. In addition to their known physicochemical characteristics, such as high surface area, mechanical strength, and ease of functionali-zation, CNTs possess pharmacokinetic properties that enable their use in targeted drug-delivery and diag-nostic systems. Through functionalization, biodistribution, cellular uptake, and circulatory time can be modulated, thereby overcoming the limitations of traditional therapies, such as low bioavailability and systemic toxicity, and enabling more robust absorption, distribution, metabolism, and excretion profiles. Targeted CNT formulations can reduce off-target exposure and improve therapeutic efficiency through targeted delivery and controlled release. Besides, conjugation of CNTs to imaging or diagnostic agents enables improved assessment of biodistribution and metabolic characteristics, which justify their use as theranostic platforms. This review describes the new developments in CNT-based drug delivery systems for cancer treatment, with particular regard to their interactions with metabolism and the importance of these interactions on drug excretion. The fact that CNTs cross biological barriers and can boost drug bio- availability highlights the importance of these nanoparticles in enhancing the effectiveness of treatment procedures and minimizing toxicity. However, safety issues, including toxicity, long-term safety, and bi- ocompatibility, are also significant impediments to clinical translation. There will be a need to address such issues by systematizing pharmacokinetic and metabolic studies to assist in developing CNT-based solutions for precision oncology.

The therapeutic efficacy and safety profile of dexmedetomidine‑containing drug Dexanest® were analyzed in neurosurgical operations (hemilaminectomy, minihemilaminectomy, ventral slot) in dogs of 8 breeds with spinal pathologies. It was shown that constant rate infusion (CRI) of Dexanes®t provides more stable sedation and reduced need for additional analgesics (10 % vs 30…40 % with other administration routes). Breed-specific features were identified: brachycephalic breeds require dose adjustment; dachshunds demonstrate delayed drug elimination; while corgis, beagles, spaniels and welsh terriers tolerate standard protocols well. The proposed breed-specific recommendations improve anesthesia safety and reduce complication risks.

Intestinal excretion (IE), one of the under-investigated mechanisms of drug elimination, has been identified as the loci of drug-drug interactions (DDIs) within the intestinal tract. Here, we employed a modified rat in situ intestinal perfusion model to examine of the drug clearance of apixaban, talinolol, and irinotecan in the short time drug recovery study. The influence of specific efflux transporter inhibitors, including P-glycoprotein (P-gp) inhibitor elacridar, multidrug resistance-associated protein 2 (Mrp2) inhibitor MK571, and breast cancer resistance protein (Bcrp) inhibitor KO143, on IE, systemic exposure and metabolite ratio were accessed using a 2.5-h constant-rate intravenous infusion. IE plays a major role in the elimination of apixaban (36 ± 14% of the total amount eliminated estimated using the sum of biliary, renal, and intestinal excretion), but only a minor role in the excretion of talinolol (11 ± 3.9%) and irinotecan (22 ± 3.1%). Efflux transporter inhibitors of P-gp/Mrp2 significantly reduced the apixaban's intestine clearance without substantially affecting its biliary excretion or metabolite ratio, accompanied by increased systemic exposure or plasma area under the curve (AUC). However, the systemic PKs of talinolol and irinotecan were not altered, likely due to low IE. The drug's IE was temperature- and dose-dependent but not intestinal segmental-dependent. The modified perfusion model provides a robust framework for characterizing intestinal clearance and assessing transporter-mediated interactions for drugs undergoing intestinal clearance following i.v. administration. Similar to other routes, intestinal clearance can be a critical elimination pathway, and apixaban is a suitable reference "victim" drug for intestinal clearance inhibition studies.

Effective precision oncology demands integration of pharmacokinetics/pharmacodynamics (PK/PD) profiling with tumor-specific genomic features. Here, we present a personalized treatment model using a patient-derived Networking Organoid Culture System (NOCS) composed of intestinal, liver, and kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of an NF1-mutant breast cancer patient. This multi-organoid system enabled individualized assessment of drug absorption, distribution, metabolism, and excretion. Integrative genomic and pathway analyses uncovered therapeutic vulnerabilities, including responsiveness to a novel exon skipping therapy targeting NF1. PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts.

It is well established that the majority of anti-cancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later stage clinical trials. The simple explanations are that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice (GLP) toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. While this is certainly hyperbole, it is true that drug efficacy often appears significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models in common use for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.

Pediatric populations differ from adults in drug elimination capacity. While current scaling methods account for enzyme and transporter maturation, they overlook comorbidities, such as biliary atresia (BA), a liver disease appearing within the first 2-8 weeks of life that can progress to cirrhosis. Such conditions may impair hepatic drug clearance, requiring dose adjustments. Physiologically based pharmacokinetic (PBPK) tools aim to address such cases and have been advocated to fill gaps in clinical data instead of less formalized and evidence-based guesswork. However, the paucity of systems data in rare disease populations has hindered the development of robust PBPK models. This study used global liquid chromatography and tandem mass spectrometry (LC-MS/MS) proteomics to quantify drug-metabolizing enzymes and transporters in diseased neonatal (n = 13) and infant (n = 12) liver samples, revealing significant expression changes in biliary atresia (BA) livers vs. controls (n = 19). Based on cohort means, CYP2A6, CYP2B6, and CYP2E1 levels were 6-17-fold higher in BA livers compared to controls, while CYP4F11 and CYP20A1 were reduced. UGT1A1, UGT2B4, and UGT2B7 showed up to 16-fold higher abundance in neonates with BA. Among transporters, ABCF1 abundance increased dramatically (46-fold), whereas B3AT/SLC4A1, ADT1/SLC25A4, and S27A5/SLC27A5 were decreased. The observed alterations suggest that assuming similar liver function in BA and non-BA patients has implications, with impact varying by drug clearance pathway. While in silico models can explore this, clinical pharmacokinetic studies in BA are essential for verification. To our knowledge, such studies are absent. Our observations underscore the urgent need for dedicated pharmacokinetic studies in BA patients to improve precision dosing.

A skin-interfaced sensor for noninvasive monitoring of pharmacokinetic and pharmacodynamic responses.

Chrono-pharmacology (often used interchangeably with chronopharmacology) examines how biological rhythms—especially circadian (≈24-hour) timing—shape drug absorption, distribution, metabolism, excretion, efficacy, and toxicity. This review synthesises contemporary mechanisms linking circadian biology to pharmacokinetics and pharmacodynamics, describes methodological principles for translating circadian insights into clinical dosing strategies, and evaluates evidence across therapeutic domains with an emphasis on cardiovascular, inflammatory, and oncologic applications. Over the last two decades, advances in molecular chronobiology have clarified that circadian clocks operate not only in the suprachiasmatic nucleus (the central pacemaker) but also in peripheral tissues such as the liver, gut, heart, immune cells, and tumours. These clocks orchestrate rhythmic transcriptional and post-translational programs that create predictable time-of-day variation in drug-processing proteins, target availability, pathway sensitivity, and repair mechanisms. Consequently, “when” a drug is taken can become as clinically meaningful as “which” drug is chosen, particularly for therapies with narrow therapeutic indices or time-sensitive targets. Finally, it outlines emerging technologies enabling individualised chronotherapy, including wearable-derived phase markers, digital phenotyping of sleep–wake behavior, and systems approaches that integrate multi-omics with pharmacology. Chrono-pharmacology reframes therapeutics as a time-aware intervention and offers a pragmatic path to optimise benefit–risk profiles without necessarily changing drug molecules—by aligning dosing with biology.

The selection and optimization of drug leads is largely driven by equilibrium parameters such as IC50 values. However, this approach does not account for the time-dependence of drug-target interactions, which is important given that drug and target concentrations fluctuate in the human body. A fundamental understanding of drug-target binding kinetics is particularly important when the formation and breakdown of the drug-target complex is slow compared to the rate of drug elimination and becomes critical when dealing with covalent drugs where the drug is irreversibly bound to the target. The parameters that define covalent inhibition, specifically kinact and KI, can be determined by quantifying target binding as a function of drug concentration and time. However, such assays are difficult to implement in early stages of drug discovery. Here, we review practical approaches to quantify irreversible inhibition, including progress-curve kinetics, multi-timepoint IC50 fitting (EPIC) for scalable library triage, intact- and peptide-level mass spectrometry to confirm adducts and sites, label-free biophysics (SPR, NMR) for orthogonal validation and washout/jump-dilution experiments to diagnose reversibility and measure residence time (τ). We then describe the translation of these microscopic rates to pharmacology through three system determinants: protein turnover, target vulnerability and pharmacokinetics using case studies from BTK, JAK3, KRASG12C and EGFR to illustrate how aligning chemistry with context yields durable efficacy. Finally, we propose reporting standards (IC50 with incubation time; kinact/KI; τ; turnover-driven occupancy) and a kinetics-first design paradigm to replace static potency with mechanism-anchored optimization of covalent inhibitors.

Physiologically based pharmacokinetic (PBPK) models are widely used in the context of personalized medicine, as they allow for the evaluation of dosing schedules and routes of administration by predicting absorption, distribution, metabolism and excretion (ADME) of drugs in biological systems. Traditionally, PBPK models have been developed and applied at the population level, enabling the characterization of predefined cohorts, which remains limited in supporting true precision dosing. In this review, we explored the increasingly common shift from population-based to individual PBPK modelling, where individuals are modelled as virtual twins (VTs). Through the inclusion of additional patient-specific data, such as demographic, physiological, phenotypic and genotypic information, models can be personalized, moving beyond traditional one-size-fits-all strategies. Overall, incorporating individual patient data (e.g., septic, psychiatric, cardiac, or neonatal populations) improves model performance. Physiological parameters, particularly renal function, show strong potential given their role in drug elimination, while demographic variables enhance predictive accuracy in certain studies. In contrast, the benefits of including cytochrome P450 (CYP) phenotypic and genotypic data remain inconsistent. We further emphasize methodologies used to evaluate model performance, with a focus on clinical validation through comparisons between predicted and observed concentration-time profiles. Key challenges, including limited sample sizes and data availability, that may compromise predictive precision, are also discussed. Finally, we highlight the potential integration of PBPK-based VTs into broader digital twin frameworks as a promising path toward clinical translation, while acknowledging the critical barriers that must be addressed to enable routine clinical implementation.

Molecular mechanistic insights into gel elimination and dissolution enhancement of small molecular drug: A case study of Lenvatinib mesylate

Applications of in vitro transporter assays for mechanistic characterization and prediction of clinical drug-drug interactions.

Morphine-6-glucuronide (M6G), the active metabolite of morphine, is currently in clinical development due to its higher analgesic activity. In humans, intravenously administered M6G was predominantly eliminated unchanged through the kidney, whereas it was excreted into the urine as parent drug as well as its metabolites morphine and M3G in normal rats. In bile-duct-cannulated rats, however, bile excretion of the parent drug was the main route of clearance. In the study, we investigated the mechanisms underlying the species differences in vivo disposition of M6G. In hepatocyte uptake assay, we showed that M6G uptake in rat hepatocytes was 75-fold higher than that in human hepatocytes. Hepatic uptake transporter phenotyping study identified M6G as a substrate for rat rOatplal, rOatpla4, rOatp1b2, as well as for human hOATP1B1 and hOATP1B3. Among these, rOatps exhibited significantly stronger uptake of M6G compared to hOATPs. Furthermore, M6G was not a substrate for the canalicular efflux transporters MDR1, hBCRP/rBcrp, hBSEP/rBsep, and hMRP2, but it was recognized by rMrp2. These findings aligned with the observation that M6G exhibited significant biliary excretion in the rat sandwich cultured hepatocyte (SCH) model, but not in the human SCH. Additionally, no species differences were observed in renal uptake mediated by OAT3. Overall, M6G underwent renal clearance in humans via glomerular filtration and active secretion primarily mediated by hOAT3. Although a portion of M6G was also eliminated through the kidney in rats, the majority was subjected to enterohepatic circulation mediated primarily by rOatps and rMrp2, leading to the formation of morphine and M3G, which were subsequently excreted in the urine. The marked difference in the uptake activities of sinusoidal transporters hOATPs/rOatps and the substrate specificity of canalicular transporters hMRP2/rMrp2 were critical factors underlying the species differences in the hepatobiliary disposition of M6G.

Effective drug delivery through the female reproductive tract (FRT) presents unique challenges due to the lack of robust predictive models for drug exposure via this route. Addressing this gap, we developed and evaluated a comprehensive whole-body physiologically based pharmacokinetic (PBPK) model that incorporates anatomical and physiological information of the FRT. This model was calibrated using both published and experimental data for the drug levonorgestrel (LNG), administered via oral, vaginal, and intrauterine routes. The PBPK model simulates drug absorption, distribution, and elimination, providing predictions of local tissue concentrations and systemic exposure. The majority of observations can be contained within or overlaid with the simulated profiles. Noteworthy is the model's capability to predict the pharmacokinetics of LNG with reasonable precision across different administration routes, thereby demonstrating its potential utility in supporting drug development and regulatory decisions. The application of this model allows for exploration of drug formulations and dosing regimens, reducing the reliance on extensive clinical trials. Furthermore, the model may potentially be used to facilitate generic drug development, and thus promote generic competition, for drug products that are important in women's health. By bridging critical knowledge gaps, this model facilitates in silico evaluation of drugs administered through the FRT, potentially fostering advancements in therapeutic strategies and patient care.

Cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins responsible for the metabolism of numerous important compounds. In humans, they are responsible for nearly 80% of oxidative reactions and approximately 50% of total drug elimination, mainly within the CYP1–CYP3 families. The CYP3A4 isoenzyme, involved in the metabolism of around 50% of drugs used in clinical practice, along with the highly polymorphic CYP2C9 and CYP2C8 genes, are key members of the cytochrome P450 subfamily. Their genetic variability, which may result in abolished, quantitatively or qualitatively altered or enhanced metabolism, varies among populations and geographical regions. This review presents the frequency and diversity of CYP2C8, CYP2C9 and CYP3A4 alleles across European countries.

Major depressive disorder is a highly prevalent psychological disorder worldwide and its main treatment is the use of Selective Serotonin Reuptake Inhibitors. However, few studies have demonstrated the relationship between the presence of genetic variants in pharmacogenes and the efficacy of these drugs, especially in populations with a unique genetic profile, such as the Indigenous peoples of the Amazon. Our study characterized the molecular profile of nine genes related to drug administration, metabolization, distribution, and elimination pathways and pharmacodynamic mechanisms of drug response through Whole Exome Sequencing applied in 64 Indigenous located in the Amazon. We compared the allele frequencies of the variants in Indigenous peoples and other world populations using Fisher's exact test carried out in RStudio v.3.5.1. We identified a total of 125 variants, of which 6 are possible new variants in our population on the HTR2A, HTR2C, CYP2D6, and CYP1A2 genes. At least 9 variants showed a significant difference in the Indigenous population compared with other populations worldwide. Our study reaffirms the unique genetic profile of the Brazilian Amazon Indigenous population and allows us to contribute population-specific variants that may serve as future pharmacogenomic biomarkers that help in the understanding of the individual genetic profiles of Indigenous people. Although the present study does not evaluate clinical drug response, the characterization of these variants provides a foundation for future studies exploring their potential impact on antidepressant efficacy in Indigenous populations and the application of this knowledge in the development of specific treatment protocols guided by pharmacogenomics.

Isoxazoline antiparasitic drugs are a new class of ectoparasiticides used in veterinary medicine for companion animals. Four active substances-fluralaner, (es)afoxolaner, lotilaner, and sarolaner-are marketed globally for flea and tick control. Isoxazolines exhibit long plasma half-lives in dogs and cats, with lotilaner reaching 30 days and sarolaner up to 41.5 days in cats. Their bioavailability varies with feeding; fasting significantly reduces lotilaner absorption. These drugs are primarily eliminated via the biliary/fecal route, with fluralaner showing a fecal elimination half-life of 3 to 12 days in felids and 6 to 38 days in canids. The European Medicines Agency has highlighted the risk of these substances contaminating ecosystems, though data on their environmental release are limited. Recent studies suggest that fluralaner and other parasiticides can be transferred to the environment via feces, urine, or pet hair. This study examined isoxazoline fecal elimination in dogs and cats. Elimination half-lives were determined in groups of five dogs or five cats per active substance. All animals received the drug according to label instructions. The estimated median half-lives were 15.5 and 22.0 days for fluralaner and lotilaner in cats, and 22.9, 24.6, 19.7, and 17.4 days for fluralaner, lotilaner, afoxolaner, and sarolaner in dogs, respectively. Fluralaner and lotilaner were still detected in feces after the end of the recommended treatment period. We used Monte Carlo simulations to assess the risk to nontarget arthropods. Environmental risk assessment indicated that dung-feeding insects could be highly exposed to isoxazoline parasiticides, with fluralaner and lotilaner having the greatest potential impact. These findings emphasize the need for further research on environmental contamination (pathways, quantitative estimate) and impact of veterinary parasiticides on nontarget species.