Insights into Inhalation Drug Disposition: The Roles of Pulmonary Drug-Metabolizing Enzymes and Transporters.

The past five decades have witnessed remarkable advancements in the field of inhaled medicines targeting the lungs for respiratory disease treatment. As a non-invasive drug delivery route, inhalation therapy offers numerous benefits to respiratory patients, including rapid and targeted exposure at specific sites, quick onset of action, bypassing first-pass metabolism, and beyond. Understanding the characteristics of pulmonary drug transporters and metabolizing enzymes is crucial for comprehending efficient drug exposure and clearance processes within the lungs. These processes are intricately linked to both local and systemic pharmacokinetics and pharmacodynamics of drugs. This review aims to provide a comprehensive overview of the literature on lung transporters and metabolizing enzymes while exploring their roles in exogenous and endogenous substance disposition. Additionally, we identify and discuss the principal challenges in this area of research, providing a foundation for future investigations aimed at optimizing inhaled drug administration. Moving forward, it is imperative that future research endeavors to focus on refining and validating in vitro and ex vivo models to more accurately mimic the human respiratory system. Such advancements will enhance our understanding of drug processing in different pathological states and facilitate the discovery of novel approaches for investigating lung-specific drug transporters and metabolizing enzymes. This deeper insight will be crucial in developing more effective and targeted therapies for respiratory diseases, ultimately leading to improved patient outcomes.

Synergistic effect of low-frequency ultrasound and antibiotics on the treatment of Klebsiella pneumoniae pneumonia in mice.

The antibiotic-resistant Klebsiella pneumoniae (Kp) has become a significant crisis in treating pneumonia. Low-frequency ultrasound (LFU) is promising to overcome the obstacles. Mice were infected with bioluminescent Kp Xen39 by intratracheal injection to study the therapeutic effect of LFU in combination with antibiotics. The counts per second (CPS) were assessed with an animal biophoton imaging system. Bacterial clearance, histopathology, and the concentrations of cytokines were determined to evaluate the therapeutic effect. LC-MS/MS was used to detect the distribution of antibiotics in the lung and plasma. LFU in combination with meropenem (MEM) or amikacin (AMK) significantly improved the behavioural state of mice. The CPS of the LFU combination group were more significantly decreased compared with those of the antibiotic alone groups. The average colony-forming units of lung tissue in the LFU combination groups were also lower than those of the antibiotic groups. Although no significant changes of cytokines (IL-6 and TNF-α) in plasma and bronchoalveolar lavage fluid were observed, LFU in combination with antibiotics showed less inflammatory damage from histopathological results compared with the antibiotic-alone groups. Moreover, 10 min of LFU treatment promoted the distribution of MEM and AMK in mouse lung tissue at 60 and 30 min, respectively, after dosage. LFU could enhance the effectiveness of MEM and AMK in the treatment of Kp-induced pneumonia, which might be attributed to the fact that LFU could promote the distribution of antibiotics in lung tissue and reduce inflammatory injury.

Development and Validation of an LC-MS/MS Method for the Quantitative Determination of Contezolid in Human Plasma and Cerebrospinal Fluid.

To develop and verify a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining contezolid in plasma and cerebrospinal fluid (CSF). Protein precipitation was performed on samples using linezolid as the internal standard. We used an Agilent EclipsePlus C18 column operating at 0.4 mL/min in conjunction with acetonitrile and water mobile phases for the LC-MS/MS analysis. Using the precursor-product ion pairs 409.15→269.14 (contezolid) and 338.14→195.1 (linezolid), multiple reaction monitoring was used to quantify the compounds. Plasma linearity range was 50.0 to 5000 ng/mL, and CSF was 20.0 to 1000 ng/mL (r2 = 0.999). The inter-batch and intra-batch precisions were ≤2.57% and ≤5.79%, respectively. Plasma recovered 92.94%, and CSF recovered 97.83%. Plasma, CSF, hemolytic plasma, and hyperlipidemic plasma all showed a coefficient of variation ≤ 7.44%. The stability and dilution integrity of this method were also acceptable. The study also demonstrated that artificial CSF can be used as a matrix for the preparation of standard curve samples. A simple and accurate method was developed and validated for the determination of contezolid concentrations in human plasma and CSF, which may be useful for monitoring the therapeutic effect of central nervous system medications.

Development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of voriconazole in human cerebrospinal fluid.

Background: A liquid chromatography-tandem mass spectrometry (LC-MS/MS). Method: For the quantification of voriconazole in human cerebrospinal fluid (CSF) was developed and validated, to guide the clinical use of voriconazole in the treatment of central nervous system infections. CSF samples were treated by protein precipitation with methanol containing fluconazole as the internal standard (IS). The supernatant was analyzed by LC-MS/MS using an Agilent EclipsePlus C18 column eluted with a methanol and water mobile phase at a flow rate of 0.4 mL min-1. Quantification was performed by multiple-reaction monitoring using the precursor and product ion pair 350/280.9 for voriconazole and 307/219.9 for fluconazole. Results: The calibration curve was linear over the range of 0.1-10.0 µg mL-1 (R2 = 0.9991). The inter-day and intra-day precisions were <4.20% and <9.97%, respectively. The recoveries for the three concentrations (0.2, 1.0, and 8.0 µg mL-1) were 99.96%, 107.00%, and 99.85%, and the matrix effects were 99.35%, 103.41%, and 99.64%, respectively. The stability under various conditions was also acceptable. The study also demonstrated that the CSF matrix could be replaced by plasma and artificial CSF. Conclusion: A simple and accurate method for the determination of voriconazole concentrations in human CSF was developed and validated, which can be used for drug monitoring in the treatment of central nervous system infections.

Evaluation of bioequivalence of two flurbiprofen axetil injections: A randomized, open-label, double-cycle, and crossover study.

Flurbiprofen is a non-steroidal anti-inflammatory drug. We evaluated the bioequivalence of a new formulation of flurbiprofen axetil for injection and the reference drug ROPION (another kind of flurbiprofen axetil injection marketed for use) in healthy Chinese subjects. This is a single-centre, randomized, open-label, single-dose, two period crossover bioequivalence study. Each subject received a single intravenous injection at the dose of 50 mg under fasting. The drug was dissolved in 100 mL normal saline, and the injection was completed in 15 minutes. There was a 7-day washout period between the two administrations. The plasma concentrations of flurbiprofen were measured by LC-MS/MS, and descriptive statistics were used to describe the safety outcomes including adverse events (AEs) and adverse drug reactions (ADRs). Twenty-four subjects were enrolled in this study. Mean values of primary PK parameters (Tmax , Cmax , AUC0-t , AUC0-∞ , λz , T1/2 ) were similar (P > 0.05). Tmax for both products is 0.3 hours. The 90% confidence intervals (CIs) for peak concentration Cmax ranged between 96.87% and 100.42%, and the area under curve AUC0-t and AUC0-∞ ranged between 99.09% and 104.29% and 98.97% and 104.29%, respectively. The 90% CIs for the geometric means and ratios of primary PK endpoints of flurbiprofen axetil injection to reference drug ranged between 98.97% and 104.29%. The adverse event rate of the test product was 8.3% and no serious adverse events (SAE) occurred in this clinical study. We concluded that the test product and the reference drug were bioequivalent and the safety was high in healthy Chinese subjects.