Extravascular Administration Research Articles

Disposition kinetics and bioavailability of doxycycline after parenteral administrations in ewes

Doxycycline is a tetracycline, which have been marketed in different species for treating infections caused by susceptible bacteria. There is limited information on the disposition kinetics of this drug in ewes and this antimicrobial may be useful against several sheep pathogens that are common causes of morbidity and economic loss. Therefore, the aim of this work was to establish the pharmacokinetics of doxycycline after intravenous (IV) and extravascular (subcutaneous (SC) and intramuscular (IM)) administrations in this species. A cross-over model was designed (n = 6). Doxycycline was dosed at 5 mg/kg for IV administration and 20 mg/kg for extravascular administrations. Non-compartmental pharmacokinetic methods were used to calculate plasma concentration-time data. The value of apparent volume of distribution (Vz) suggests a moderate distribution of this antibiotic in sheep, with a value of 0.84 L/kg. The maximum concentrations achieved after extravascular administrations (Cmax) were similar, with no significant differences between the two routes of administration (IM and SC). However, doxycycline absorption was slower after SC administration than after IM administration, taking twice as long to reach maximum plasma concentration (tmax). Bioavailabilities after extravascular routes of administration were low and after IM administration doxycycline caused lameness in all animals. Therefore, the SC administration showed a better profile with respect to pharmacokinetic properties and safety. Future studies on the susceptibility of isolated sheep pathogens to doxycycline are needed to establish appropriate dosing regimens.

Pharmacokinetics of Doxycycline in Plasma and Milk after Intravenous and Intramuscular Administration in Dairy Goats.

Doxycycline is a second-generation tetracycline, marketed in different species for treating infections caused by susceptible bacteria. Little information is available on the pharmacokinetics of doxycycline in lactating goats. The objective of this study was to establish the disposition kinetics of doxycycline after parenteral administration (intravenous and intramuscular) in dairy goats and its elimination in milk. A cross-over model was designed (n = 6). Doxycycline was dosed at 5 mg/kg for intravenous administration and 20 mg/kg for extravascular administrations. Noncompartmental pharmacokinetic methods were used to calculate plasma concentration-time data. The Vz value suggests a moderate distribution of this antibiotic in goats, with a value of 0.85 L/kg. A low bioavailability (F = 45.60%) of doxycycline following an intramuscular injection was observed, with all animals exhibiting signs of lameness. Doxycycline rapidly crossed the blood-milk barrier, but exposure to the antimicrobial and the concentrations reached in milk were lower than those obtained in plasma. Although PK/PD ratios may be low with the pharmacokinetic data obtained with this formulation of doxycycline, at this dose and route of administration, doxycycline after IM administration could be useful for infections by moderate or highly susceptible bacteria in the mammary gland of goats. However, it may be necessary to test different doses of doxycycline or other routes of administration to achieve better surrogate markers and to establish repeated dosing regimens and clinical efficacy.

Construction of an in vitro simulated one compartment extravascular administration model and its comparison with classic in vitro administration model in copper chloride induced HepG2 cell death

In this study, we designed an in vitro administration device based on compartment model theory and utilized it to construct an in vitro simulated one compartment extravascular administration model of copper chloride. Within the Cmax range of 3.91–1000.00 μM, the measured concentration-time curves of the simulated one compartment extravascular administration model almost coincide with the corresponding theoretical curves. The measured values of toxicokinetic parameters, including ke, T1/2, ka, T1/2a, Tmax, Cmax, CL, and AUC0-∞ are close to the corresponding theoretical values. The fitting coefficients are >0.9990. In simulated one compartment extravascular administration and classic in vitro administration, copper chloride dose-dependently induced HepG2 cell death. When Cmax/administration concentration is equal, classic in vitro administration induces a higher cell death rate than simulated one compartment extravascular administration. However, there is no significant difference in inducing cell death between the two administration models when area under the curve is equal. In conclusion, the device designed in this study can be used to in vitro simulate one compartment extravascular administration, making in vitro toxicity testing more similar to in vivo scenarios. There are differences in copper chloride induced HepG2 cell death between simulated one compartment extravascular administration and classic in vitro administration.

Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models.

An abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease. We identified plasma insulin-like growth factor 1 (IGF1) as an independent risk factor in patients with AAA by correlating plasma IGF1 with risk. Smooth muscle cell- or fibroblast-specific knockout of Igf1r, the gene encoding the IGF1 receptor (IGF1R), attenuated AAA formation in two mouse models of AAA induced by angiotensin II infusion or CaCl2 treatment. IGF1R was activated in aortic aneurysm samples from human patients and mice with AAA. Systemic administration of IGF1C, a peptide fragment of IGF1, 2 weeks after disease development inhibited AAA progression in mice. Decreased AAA formation was linked to competitive inhibition of IGF1 binding to its receptor by IGF1C and modulation of downstream alpha serine/threonine protein kinase (AKT)/mammalian target of rapamycin signaling. Localized application of an IGF1C-loaded hydrogel was developed to reduce the side effects observed after systemic administration of IGF1C or IGF1R antagonists in the CaCl2-induced AAA mouse model. The inhibitory effect of the IGF1C-loaded hydrogel administered at disease onset on AAA formation was further evaluated in a guinea pig-to-rat xenograft model and in a sheep-to-minipig xenograft model of AAA formation. The therapeutic efficacy of IGF1C for treating AAA was tested through extravascular delivery in the sheep-to-minipig model with AAA established for 2 weeks. Percutaneous injection of the IGF1C-loaded hydrogel around the AAA resulted in improved vessel flow dynamics in the minipig aorta. These findings suggest that extravascular administration of IGF1R antagonists may have translational potential for treating AAA.

CPhaMAS: An online platform for pharmacokinetic data analysis based on optimized parameter fitting algorithm

Background and objectiveClinical pharmacological modeling and statistical analysis software is an essential basic tool for drug development and personalized drug therapy. The learning curve of current basic tools is steep and unfriendly to beginners. The curve is even more challenging in cases of significant individual differences or measurement errors in data, resulting in difficulties in accurately estimating pharmacokinetic parameters by existing fitting algorithms. Hence, this study aims to explore a new optimized parameter fitting algorithm that reduces the sensitivity of the model to initial values and integrate it into the CPhaMAS platform, a user-friendly online application for pharmacokinetic data analysis. MethodsIn this study, we proposed an optimized Nelder-Mead method that reinitializes simplex vertices when trapped in local solutions and integrated it into the CPhaMAS platform. The CPhaMAS, an online platform for pharmacokinetic data analysis, includes three modules: compartment model analysis, non-compartment analysis (NCA) and bioequivalence/bioavailability (BE/BA) analysis. Our proposed CPhaMAS platform was evaluated and compared with existing WinNonlin. ResultsThe platform was easy to learn and did not require code programming. The accuracy investigation found that the optimized Nelder-Mead method of the CPhaMAS platform showed better accuracy (smaller mean relative error and higher R2) in two-compartment and extravascular administration models when the initial value was set to true and abnormal values (10 times larger or smaller than the true value) compared with the WinNonlin. The mean relative error of the NCA calculation parameters of CPhaMAS and WinNonlin was <0.0001 %. When calculating BE for conventional, high-variability and narrow-therapeutic drugs. The main statistical parameters of the parameters Cmax, AUCt, and AUCinf in CPhaMAS have a mean relative error of <0.01% compared to WinNonLin. ConclusionsIn summary, CPhaMAS is a user-friendly platform with relatively accurate algorithms. It is a powerful tool for analysing pharmacokinetic data for new drug development and precision medicine.

Pharmacokinetics of dimeric dipeptide mimetic of nerve growth factor GC-2 in rats. Part 1. Single and multiple intravascular and extravascular administration. Testing the hypothesis of linearity of pharmacokinetics

The pharmacokinetics of dimeric dipeptide mimetic of nerve growth factor GC-2 in the rat blood plasma after different routes of administration was studied. The drug was administered at dose of 150 mg/kg by single and repeatedly. After single intravenous and intraperitoneal injection, GC-2 was detected for 2 h, its half-life was 0.4 h. GC-2 absolute bioavailability after single intraperitoneal injection was 84.62 %, that indicates the prospect of development its injectable (intramuscularly) dosage form. After 4-fold (1.5 h dosing interval) intraperitoneal injection dose-independent pharmacokinetic parameters of GC-2 practically do not change compared to single administration. This indicates that GC-2 is not accumulated in the body of rats. The hypothesis of the linearity of the pharmacokinetics of GC-2 in the rats blood plasma after single intraperitoneal administration at doses of 50, 100 and 150 mg/kg was tested. It was found that the kinetics of GC-2 in the rat blood plasma is linea.

Pharmacokinetics of robenacoxib following single intravenous, subcutaneous and oral administrations in Baladi goats (Capra hircus).

The purpose of this study was to assess the pharmacokinetics of robenacoxib (RX), a COX-2 selective non-steroidal anti-inflammatory drug, in goats after single intravenous (IV), subcutaneous (SC) and oral (PO) administrations. 5-month-old healthy female goats (n = 8) were used. The animals were subjected to a three-phase, two-dose (2 mg/kg IV, 4 mg/kg SC, PO) unblinded, parallel study design, with a four-month washout period between the IV and SC treatment, and a one-week period between the SC and PO treatment. Blood was drawn from the jugular vein in heparinized vacutainer tubes at 0, 0.085 (for IV only), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10 and 24 h. Plasma RX concentrations were measured using HPLC coupled to a UV multiple wavelength detector, and the data were pharmacokinetically analysed using ThothPro™ 4.3 software in a non-compartmental approach. Following IV administration, terminal elimination half-life, volume of distribution and total clearance were 0.32 h, 0.24 L/kg and 0.52 L/h/kg, respectively. For SC and PO, the mean peak plasma concentrations were 2.34 and 3.34 μg/mL at 1.50 and 0.50 h, respectively. The t1/2λz was significantly different between the IV and the extravascular (EV) administrations (0.32 h IV vs 1.37 h SC and 1.63 h PO), suggesting the occurrence of a flip-flop phenomenon. The significant difference in Vd values between IV (0.24 L/kg) and EV (0.95 L/kg SC and 1.71 L/kg; corrected for F %) routes might have also triggered the t1/2λz difference. The absolute average SC and PO bioavailability were high (98% and 91%, respectively). In conclusion, the IV administration of RX might not be suitable for goats, due to its short t1/2λz. The EV routes, however, appear to be convenient for the drug's occasional use.

A novel method to estimate the absorption rate constant for two-compartment model fitted drugs without intravenous pharmacokinetic data.

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (ka) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the ka values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (kmax). The accuracy of the direct method in ka estimation was determined using the setting parameters (k12, k21, and k10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of ka estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the ka values of these drugs were accurately estimated using the direct method based on good correlations between the ka values and other PK parameters that reflected the absorption properties of drugs in vivo (Tmax, Cmax, and Cmax/AUC0-t). This novel method can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment.

Pharmacokinetics and pharmacodynamics of intramuscular dexmedetomidine in dogs.

To determine the pharmacokinetics and pharmacodynamics of dexmedetomidine after IM administration in dogs. 6 healthy adult purpose-bred dogs (3 males, 3 females) with a mean ± SD body weight of 25.2 ± 1.8 kg. Each dog received 10 µg/kg dexmedetomidine, IM. Heart rate and respiratory rate were counted via cardiac auscultation and visual assessment of chest excursions. Sedation was assessed utilizing 2 sedation scoring systems. Plasma concentrations were determined using ultra performance liquid chromatography-mass spectrometry. Plasma concentrations versus time data after IM dexmedetomidine were analyzed using noncompartmental analysis for extravascular administration. Over the first 2 hours following IM injection of dexmedetomidine, plasma concentrations fluctuated in each dog. The geometric mean (range) maximum plasma concentration was 109.2 (22.4 to 211.5) ng/mL occurring at 20.5 (5 to 75) minutes, and the mean half-life was 25.5 (11.5 to 41.5) minutes. Heart rate was significantly lower than baseline from 30 minutes to 2 hours postdexmedetomidine administration, and respiratory rate was significantly lower than baseline from 45 minutes to 1.75 hours. Dogs were significantly more sedated from 30 minutes to 1.5 hours postdexmedetomidine administration. Median time to onset of sedation was 7.5 minutes (range, 2 to 10 minutes), and median time to peak sedation was 30 minutes (range, 15 to 60 minutes). Variations in plasma concentrations occurred in all dogs for the 2 hours postinjection of dexmedetomidine at 10 µg/kg, IM. This was likely due to alterations in absorption due to dexmedetomidine-induced local vasoconstriction. Despite variable plasma concentrations, all dogs were sedated following IM dexmedetomidine administration.

Engineering Lipid Spherulites for the Sustained Release of Highly Dosed Small Hydrophilic Compounds.

Currently, there is a lack of parenteral sustained release formulations for the delivery of highly dosed small hydrophilic drugs. Therefore, parenteral lipid spherulites are engineered capable of entrapping large amounts of such compounds and spontaneously releasing them in a sustained fashion. A library of spherulites is prepared with a simple green process, using phosphatidylcholine (PC) and/or phosphatidylethanolamine (PE), nonionic surfactants and water. The vesicle formulations exhibiting appropriate size distribution and morphology are selected and loaded with 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), ((OEG2 )2 -IP4), an inositol phosphate derivative currently under clinical evaluation for the treatment of aortic valve stenosis. The loading efficiency of spherulites is up to 12.5-fold higher than that of liposomes produced with the same materials. While the PC-containing vesicles showed high stability, the PE spherulites gradually lost their multilayer organization upon dilution, triggering the active pharmaceutical ingredient (API) release over time. In vitro experiments and pharmacokinetic studies in rats demonstrated the ability of PE spherulites to increase the systemic exposure of (OEG2 )2 -IP4 up to 3.1-fold after subcutaneous injection, and to completely release their payload within 3-4 d. In conclusion, PE spherulites represent a promising lipid platform for the extravascular parenteral administration of highly dosed small hydrophilic drugs.

Formulation of Chitosan Microparticles for Enhanced Intranasal Macromolecular Compound Delivery: Factors That Influence Particle Size during Ionic Gelation.

Therapeutic macromolecules (e.g., protein and peptide drugs) present bioavailability challenges via extravascular administration. The nasal route presents an alternative non-invasive route for these drugs, although low bioavailability remains challenging. Co-administration of permeation enhancers is a promising formulation approach to improve the delivery of poorly bioavailable drugs. The aim of this study was to prepare and characterize chitosan microparticulate formulations containing a macromolecular model compound (fluorescein isothiocyanate dextran 4400, FD-4) and a bioenhancer (piperine). Ionic gelation was used to produce chitosan microparticle delivery systems with two distinct microparticle sizes, differing one order of magnitude in size (±20 µm and ±200 µm). These two microparticle delivery systems were formulated into thermosensitive gels and their drug delivery performance was evaluated across ovine nasal epithelial tissues. Dissolution studies revealed a biphasic release pattern. Rheometry results demonstrated a sol-to-gel transition of the thermosensitive gel formulation at a temperature of 34 °C. The microparticles incorporating piperine showed a 1.2-fold increase in FD-4 delivery across the excised ovine nasal epithelial tissues as compared to microparticles without piperine. This study therefore contributed to advancements in ionic gelation methods for the formulation of particulate systems to enhance macromolecular nasal drug delivery.

Pharmacokinetic model for extravascular administration based on uncertain differential equation

Pharmacokinetic model for extravascular administration based on uncertain differential equation

An Effective QWBA/UHPLC-MS/Tissue Punch Approach: Solving a Pharmacokinetic Issue via Quantitative Met-ID.

Methods to provide absolute quantitation of the administered drug and corresponding metabolites in tissue in a spatially resolved manner is a challenging but much needed capability in pharmaceutical research. Quantitative Whole-Body Autoradiography (QWBA) after a single- dose intravenous (3 mg/kg) and extravascular (30 mg/kg) administrations of an in vitro metabolically stable test compound (structure not reported here) indicated quick tissue distribution and excretion. Good bioavailability and short in vivo half-lives were determined formerly for the same test compound. For closing gaps in the understanding of pharmacokinetic data and in vitro results, radioactive hot spots on whole-body tissue sections had been profiled. Punches from selected tissue regions containing high radioactivity in the tissue sections previously analyzed by QWBA were extracted by a highly organic solvent and analyzed without any consecutive sample preparation step, applying Ultra High Performance Liquid Chromatography- Mass Spectrometry (UHPLC-MS) and off-line radioanalysis to maximize signal levels for metabolite identification and profiling. The analysis revealed that the test compound was metabolized intensively by phase I reactions in vivo and the metabolites formed were excreted in bile and urine. The predominant metabolites showed abundant signal intensities both by MS and by radioanalysis but the MS signal intensities generally underestimated the real abundances of metabolites relative to the unchanged drug. This work illustrates that maximizing the sensitivity of tissue punch radioanalysis and the combination with UHPLC-MS leads to a better insight into pharmacokinetic processes by providing quantitative data with high molecular selectivity.

The influence of the site of drug administration on florfenicol pharmacokinetics in turkeys

Florfenicol is a broad-spectrum antibacterial drug used in the treatment of farm animals, including poultry. This drug is poorly soluble in water, therefore, administration in drinking water may lead to high variability of concentrations in treated individuals. The use of injection preparations, however, requires individual administration and may have a negative effect on the quality of the carcass. In addition, the renal portal system in birds may reduce the bioavailability of the drug administered in the caudofemoral region of the body. The aim of this study was to compare the pharmacokinetics of florfenicol in turkeys after a single intravenous, intramuscular, and subcutaneous administration at a dose of 15 mg/kg body weight. Additionally, to evaluate the effect of renal portal system on drug kinetics, the intramuscular administration was divided into pectoral and caudofemoral administration. The study showed that the area under the concentration-time curve (AUC) was similar regardless of the route of administration. The mean values for clearance and volume of distribution were 0.33 L/kg/h and 0.92 L/kg, respectively. The mean residence time (MRT) was 2.87 h for an intravenous bolus, while for the extravascular administrations it was approx. 5.5 h. The elimination half-life was approx. 4 h regardless of the route of administration. The maximum plasma concentration did not differ statistically between intramuscular (approx. 6.8 mg/L) and subcutaneous (8.2 mg/L) administrations, while the time to appear for this concentration was the longest for caudofemoral administration (1.5 h). The bioavailability was 88.64% for subcutaneous administration, 77.95% for pectoral administration and 85.30% for caudofemoral administration. Overall, all 3 routes of extravascular administration allowed for efficient drug absorption. There was no evidence of an influence of the renal portal system on the kinetic parameters of the drug administered to the lower extremities of the body.

Pharmacokinetics of Tildipirosin in Ewes after Intravenous, Intramuscular and Subcutaneous Administration.

Simple SummaryPneumonia is a significant cause of death in sheep flocks. Thus, antibiotics are essential for the treatment of bacterial pneumonia to reduce morbidity and mortality, but few drugs are specifically labeled for clinical use in sheep. Many of the antimicrobial clinical prescriptions that occur in sheep are classified as extra-label use, with dosage, administration frequency, indications, and drug withdrawal times usually being extrapolated from information reported in other species. Thus, the objective of this study was to determine the disposition kinetics of tildipirosin after intravenous, intramuscular, and subcutaneous administration in sheep. Throughout the experiment, all ewes were healthy and no adverse reactions were recorded. The apparent volume of distribution was high, indicating a wide distribution in the body, which can be attributed to a significant fraction of tildipirosin inside the cells, and its expected activity against intracellular bacteria. Following intramuscular administration, tildipirosin was rapidly absorbed even to a greater extent when compared to subcutaneous administration. Most of the adsorbed tildipirosin after intramuscular and subcutaneous administrations were available in the body (>70%). In brief, the excellent tolerability of this formulation and the suitable disposition of tildipirosin in the body makes it an alternative for sheep use, in conditions where the administration of antibiotics is needed to observe desired effects with the benefits of scant manipulation of animals.A single-dose disposition kinetics for tildipirosin was evaluated in clinically healthy ewes (n = 6) after intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration of a commercial formulation. Tildipirosin concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Plasma concentration-time data was calculated by non-compartmental pharmacokinetic methods. The apparent volume of distribution (Vz) of tildipirosin after IV administration was 5.36 ± 0.57 L/kg suggesting a wide distribution in tissues and inside the cells. The elimination half-life (t½λz) was 17.16 ± 2.25, 23.90 ± 6.99 and 43.19 ± 5.17 h after IV, IM and SC administration, respectively. Following IM administration, tildipirosin was rapidly absorbed (tmax = 0.62 ± 0.10 h) even to a greater extent than after SC administration. Time to reach peak concentration (tmax) and peak plasma concentrations (Cmax) differed significantly, but both parameters showed a more significant variability after SC than after IM administration. Bioavailabilities after extravascular administration were high (>70%). Therefore, given general adverse reactions that were not observed in any ewe and favourable pharmacokinetics, tildipirosin could be effective in treating bacterial infections in sheep.

Mesenchymal stromal cell therapeutic potency is dependent upon viability, route of delivery, and immune match

AbstractCulture-adapted bone marrow mesenchymal stromal cells (MSCs) deploy paracrine anti-inflammatory and tissue regenerative functionalities that can be harnessed as a living cell pharmaceutical product. Independent of clinical indication, a near majority of human clinical trials administer MSC IV, often with an allogeneic MSC cell product immediately after thawing from cryostorage. Despite hundreds of studies in a wide assortment of inflammatory, degenerative, and acute tissue injury syndromes, human clinical outcomes often fail to mirror promising rigorously conducted preclinical animal studies. Using a mouse model of toxic colitis, we demonstrate that replication fit MSCs harvested in log phase of growth have substantial impact on colitis clinical and pathologic endpoints when delivered subcutaneously or intraperitoneally, whereas the maximum tolerated IV bolus dosing failed to do so. We also demonstrate that heat-inactivated MSCs lose all therapeutic utility and the observation is mirrored by use of viable MSC administered immediately postthaw from cryostorage. Using luciferase transgenic MSC as donor cells, we demonstrate that transient in vivo engraftment is severely compromised when MSCs are dead or thawed and further demonstrate that MSC redosing is feasible in relapsing colitis, but only syngeneic MSCs lead to sustained improvement of clinical endpoints. These data support the notion that pharmaceutical potency of MSC requires viability and functional fitness. Reciprocally, IV administration of thawed MSC products may be biased against positive clinical outcomes for treatment of colitis and that extravascular administration of syngeneic, fit MSCs allows for effect in a recurrent therapy model.

Pkweb: An online application for pharmacokinetic data analysis

Abstract This research presents a web-based application, pkweb ( https://pkweb.hhra.net ), with a user-friendly interface and a range of functions for pharmacokinetic (PK) data analysis. Capabilities include simulation of PK data, which integrates 27 modules (e.g., intravenous (IV) bolus injection, IV infusion and extravascular administration) and modeling the fitness of PK data. The pkweb tool provides different solutions for various conditions, such as compartmental analysis (CA) under single dosing, non-compartmental analysis (NCA) under single dosing and CA under multiple dosing. Compared to other tools, a unique feature of this tool is the ability to set boundaries for the parameters of each model. This newly released application promises to facilitate both toxicokinetic and pharmacokinetic data analysis.

A New Method for the Estimation of Absorption Rate Constant in Two-Compartment Model by Extravascular Administration

This article describes a new method of estimating the absorption rate constant (ka) of a 2-compartment model with extravascular administration, which is called an alternative method. The method was based on approximating the distribution and elimination phases of a 2-compartment model to the elimination phase of a one-compartment model. By using the model equation tmax=lnka−ln(k10+k12)ka−(k10+k12), first, we obtained the peak time (tmax) and the sum value of the first-order elimination rate constant (k10) and the distribution rate constant (k12), then the iterative method was used to obtain estimated value. And the estimation results were compared with the results obtained by the Loo-Riegelman and statistical moment methods and the factors affecting the estimation results of alternative method were explored. Finally, verification experiments were carried out with actual data in the literature. In general, a good estimation effect on the value of ka in the extravascular administration of the 2-compartment model was obtained by this method, with less errors compared with the commonly used 2 other methods (p < 0.05). Changes in k12, k10, ka, and another distribution rate constant (k21) all influenced the estimation results. The alternative method also showed good results in estimating ka of compounds in the literature.

Pharmacokinetic profiles of levofloxacin after intravenous, intramuscular and subcutaneous administration to rabbits (Oryctolagus cuniculus).

Levofloxacin pharmacokinetic profiles were evaluated in 6 healthy female rabbits after intravenous (I/V), intramuscular (I/M), or subcutaneous (S/C) administration routes at a single dose of 5 mg/kg in a 3 × 3 cross-over study. Plasma levofloxacin concentrations were detected using a validated Ultra Performance Liquid Chromatography method with a fluorescence detector. Levofloxacin was quantifiable up to 10 h post-drug administration. Mean AUC0-last values of 9.03 ± 2.66, 9.07 ± 1.80, and 9.28 ± 1.56 mg/h*L were obtained via I/V, I/M, and S/C, respectively. Plasma clearance was 0.6 mL/g*h after I/V administration. Peak plasma concentrations using the I/M and S/C routes were 3.33 ± 0.39 and 2.91 ± 0.56 µg/mL. Bioavailability values, after extravascular administration were complete, - 105% ± 27% (I/M) and 118% ± 40% (S/C). Average extraction ratio of levofloxacin after I/V administration was 7%. Additionally, levofloxacin administration effects on tear production and osmolarity were evaluated. Tear osmolarity decreased within 48 h post-drug administration. All 3 levofloxacin administration routes produced similar pharmacokinetic profiles. The studied dose is unlikely to be effective in rabbits; however, it was calculated that a daily dose of 29 mg/kg appears effective for I/V administration for pathogens with MIC < 0.5 µg/mL.

A Modified Compartmental Pharmacokinetic Model of Enterohepatic Circulation for Simvastatin in Healthy Mexican Subjects. A Pilot Study

Enterohepatic circulation (EHC) is a process that many drugs go through, in which, after extravascular administration, they are absorbed in the intestine, secreted in the bile and then reabsorbed during one or more circulation cycles that alter plasmatic concentrations of said drugs. The aim of this study was to compare a new pharmacokinetic model of EHC with the classic model of extravascular administration after administering Simvastatin. A single-center, randomized, controlled, prospective, longitudinal, single-dose, cross-over study was performed with a 7-day washout period, in healthy Mexican subjects. The plasma samples obtained were quantified with HPLC-MS / MS using a validated analytical method. Cmax, tmax, AUC0-24h and AUC0-∞ were determined, and both models were compared with the Akaike Information Criterion (AIC) and r^2. Results show that the pharmacokinetic parameters calculated with the EHC model are fairly similar to those obtained with the trapezoidal model, even more so than those obtained with the classic model. The AIC and r^2 criteria were lower for the EHC model (AIC=11.256 and 12.555, r^2=0.568 and 0.440) vs the classic model (AIC=9.382 and 9.195, r^2= 0.884 and 0.922). In conclusion, a new pharmacokinetic model for EHC was developed, and results confirmed that it adjusts well to experimental data, offering an alternative way to calculate Cmax, tmax and AUC0-t, and can also be adapted to other drugs that exhibit EHC as well.