Kinetics Of Plasma Concentrations Research Articles

A physiologically-based pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites.

Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.

Microneedle-mediated transdermal delivery of naloxone hydrochloride for treatment of opioid overdose

Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p < 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment.

Image-guided mathematical modeling for pharmacological evaluation of nanomaterials and monoclonal antibodies.

While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug‐loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size‐dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non‐invasive in vivo imaging modalities. This allows for visualization and quantification of the whole‐body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non‐invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state‐of‐the‐art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities.This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseDiagnostic Tools > in vivo Nanodiagnostics and ImagingNanotechnology Approaches to Biology > Nanoscale Systems in Biology

Pharmacokinetics and metabolism of jatrorrhizine, a gastric prokinetic drug candidate

Jatrorrhizine, a protoberberine alkaloid derived from Coptis chinensis, is currently under investigation as a natural gastric prokinetic drug candidate. In vitro and in vivo studies were conducted to characterize its pharmacokinetics and metabolism. After intravenous administration, the plasma concentration kinetics and major metabolites in rats were investigated. The metabolic kinetics, key cytochrome P450 enzymes and UDP-glucuronosyltransferase isoforms (UGTs) of jatrorrhizine were studied in rat liver microsomes (RLMs). After intravenous administration, plasma jatrorrhizine concentrations showed a biphasic decline, dose-independent clearance and half-life of terminal elimination phase, and a relatively large distribution volume. The metabolic pathway for the conversion of jatrorrhizine was important for its elimination. In addition, the demethylated and glucuronidated products were found to be the major metabolites in rats. The enzyme kinetics for both demethylation and glucuronidation were fitted to the hyperbolic Michaelis-Menten equation in RLMs. CYP3A1/2 and CYP2D2 were mainly responsible for demethylation, and UGT 1A1 and 1A3 were responsible for glucuronidation in RLMs. The metabolic properties of jatrorrhizine suggest multiple metabolic pathways. These results will contribute to promote further research and development of jatrorrhizine.

Estimating Human Drug Oral Absorption Kinetics from Caco-2 Permeability Using an Absorption-Disposition Model: Model Development and Evaluation and Derivation of Analytical Solutions for ka and Fa

Intestinal transcellular permeability (P(m)), measured across cell lines such as Caco-2 cells in vitro, is often used for assessing oral drug absorption potential in humans. However, the quantitative link between in vitro permeability and apparent in vivo absorption kinetics, based on drug appearance in plasma, is poorly understood. In the current study, a novel absorption-disposition kinetic model that links traditional pharmacokinetic and mass transfer models was developed. Analytical solutions of k(a) and F(a) were deduced, and using Caco-2 permeability, F(a) in humans was predicted for 51 structurally diverse compounds. Predicted F(a) values were similar to and correlated highly with their corresponding experimental values with an average error of 1.88 +/- 1.06% (-17 to 22%) and r2 = 0.934. Simulated concentration profiles for 17 of 18 drugs corresponded to observed plasma concentration profiles in healthy volunteers. The equilibrium solution for k(a) (k(a,eq)) was found to be a key determinant of F(a), whereas under sink conditions, k(a) is likely to be a determinant of plasma concentration kinetics. The current version of the model offers a quantitative approach for predicting human oral absorption kinetics from in vitro permeability. It also establishes, for the first time, a quantitative link between P(m) and k(a) and between k(a,eq) and F(a). This will facilitate better in vitro or in situ-in vivo correlations since it establishes a basis for incorporating permeability coefficients from the various experimental formats based on drug loss or appearance that are commonly used in the laboratory for permeability determination.

Central analgesic effect of acetaminophen but not of aspirin

The central nervous system effect of acetaminophen (paracetamol) and acetylsalicylic acid was investigated in healthy volunteers according to a crossover, double-blind, and placebo-controlled design. Ten subjects received, by intravenous route, a placebo, 1 gm acetaminophen, and 1 gm acetylsalicylic acid. Analgesia was assessed by measurement of the subjective pain threshold and the objective nociceptive flexion reflex threshold in response to selective transcutaneous electrical stimulations. A close correlation was observed between subjective and objective pain thresholds. Acetaminophen increased both thresholds for more than 4 hours (24% and 23% of baseline value at 120 minutes, respectively; p less than 0.001, ANOVA). In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These findings show that acetaminophen-induced analgesia is centrally mediated, in contrast to aspirin. The time delay between plasma concentration kinetics and acetaminophen analgesic effect is another argument in favor of its direct action on the central nervous system.

Methotrexate and 7-hydroxy-methotrexate pharmacokinetics following intravenous bolus administration and high-dose infusion of methotrexate

The pharmacokinetics of methotrexate and 7-hydroxy-methotrexate were studied in patients undergoing very high-dose methotrexate monotherapy. The patients received, first, two methotrexate intravenous bolus test doses (50 mg/m 2 ) one with and one without concomitant administration of folinic acid (15 mg every 6 h) in a random sequence, and, second, an 8 h infusion, individualized to achieve a peak plasma concentration of 5 × 10 −4 M methotrexate (infusion rates > 1000 mg/h). Methotrexate and 7-hydroxy-methotrexate concentrations were measured by specific radioimmunoassays and the data were analysed simultaneously by an integrated pharmacokinetic model. Following test dose administration, methotrexate and 7-hydroxy-methotrexate plasma concentration kinetics were best described by assuming that methotexate elimination (and 7-hydroxy-methotrexate formation) occurred from a peripheral compartment reaching rapid equilibrium with the plasma. Folinic acid administration did not influence the disposition of either compound. Following the infusion, a significant ( P < 0.01) decrease of methotrexate total plasmatic clearance occurred without modification of 7-hydroxy-methotrexate formation and elimination.

Penbutolol: beta-adrenoceptor interaction and the time course of plasma concentrations explain its prolonged duration of action in man.

Beta-adrenoceptor binding of (-) penbutolol and its active metabolite 4-hydroxy-penbutolol to rat reticulocyte membranes was shown in the presence of native human plasma. Due to the high plasma protein binding (approximately 99%) the apparent Ki-values of penbutolol were shifted 100-fold to the right after inclusion of plasma in the assay; the Ki was approximately 40-70 ng/ml. That value is comparable to the IC50-values calculated from clinical studies. The interaction of 4-hydroxy-penbutolol with beta-adrenoceptors was not affected to the same extent by inclusion of plasma protein binding approximately 80%, apparent Ki-value approximately 7 ng/ml. Thus, the active metabolite of penbutolol displays higher potency at beta-adrenoceptors in vitro due to its lesser degree of plasma protein binding. A prediction procedure for antagonist activity after penbutolol administration using beta-adrenoceptor interaction and plasma concentration kinetics suggests that, in addition to a rapid elimination process from human plasma, a slow elimination phase of penbutolol (or an active metabolite) is necessary to explain the long duration of action observed in clinical studies after a single oral dose. Inhibition in vitro of beta-adrenoceptor binding by plasma samples obtained after oral administration of 40 mg penbutolol to 3 healthy volunteers indicated a biphasic concentration-time profile of the antagonist in plasma and was in accordance with the time course of the reported reduction in exercise tachycardia. Finally, plasma concentrations of penbutolol equivalents derived from the receptor assay were in the range of penbutolol concentrations detected by physico-chemical methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of the Redistribution Phenomenon after Extracorporeal Elimination

Evaluation of the efficiency of extracorporeal elimination is rendered difficult by the rebound phenomenon which may occur in plasma concentrations after hemodialysis, hemoperfusion, or plasma exchange. The term clearance, derived from the extraction rate, has the drawback that it is often based on the incompatible terms plasma concentration and blood flow. To avoid these difficulties, clearance may be calculated from kinetics of plasma concentrations. But this approach will lead to an overestimation of the eliminative efficiency, because plasma concentrations may decline faster than tissue levels, which will be indicated by the rebound phenomenon. The rebound is due to a redistribution from tissue into plasma and follows 2-compartment kinetics. However, the amount removed by extracorporeal elimination reflects the redistribution phenomenon and, simultaneously, can be used to evaluate the absolute efficiency. The amount removed can be derived from 1-compartment kinetics if redistribution can be neglected, and from 2-compartment kinetics if a redistribution takes place. The amount removed can also be evaluated using model- independent approaches, which may be applied even if sustained absorption or proliferation must be assumed. According to these approaches, the removed amount is given by graphic extrapolation, and it can be calculated from extracorporeal clearance and from concentrations in the removed fluid, or it can be eluted from the extracorporeal device.

Simple and reliable radioreceptor assay for beta-adrenoceptor antagonists and active metabolites in native human plasma.

A radioreceptor assay (RRA) for the assay of beta-adrenoceptor antagonists in native human plasma is described. The hydrophilic antagonist 3H-CGP 12177 was used as the radioligand. In contrast to the hydrophobic radioligand 3H-dihydroalprenolol, which was investigated in parallel, the beta-adrenoceptor binding of 3H-CGP 12177 by rat reticulocyte membranes was found not to be affected by inclusion of increasing proportions (0-66% of incubation volume) of human plasma in the assay. Thus, solvent extraction of drug and/or active metabolites was not necessary to avoid binding of the radioligand tracer to plasma added in the RRA. The assay of unprocessed samples was possible. Drug concentrations in plasma after oral administration of propranolol (240 mg) or carteolol (30 mg) to 6 healthy volunteers were measured by the RRA and in parallel by a chemical method. The results from both methods agreed when the plasma concentration kinetics of propranolol were investigated (elimination half-life:3.9 h). In contrast, plasma concentrations of carteolol were consistently higher according to the RRA after oral administration of the drug. Identical concentrations, however, were found by the RRA and chemical method using plasma samples spiked with carteolol. Plasma concentrations of carteolol detected by the chemical method decline monoexponentially (elimination half-life: 5.4 h). A similar half-life of elimination for parent drug was found by the RRA (5.9 h), but an additional term describing the appearance of an active metabolite was necessary to account for the biphasic drug elimination (elimination half-life of metabolite: 17.3 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the methadone-alcohol interaction. I. Alterations of plasma concentration kinetics.

Clinical anecdotal reports have indicated a probably additive and/or synergistic response to the co-ingestion of ethyl alcohol and methadone. This study investigated the possible explanations for this observations, which may be associated with alterations of the plasma concentration dynamics of methadone and alcohol in the rat. Plasma concentrations of ethanol, methadone or both were followed over an eight hour period following substance administration. GC/FID and GC/MS were employed to quantify ethanol and methadone, respectively. The results of this study indicated that ethyl alcohol significantly increased peak methadone concentrations. Further, methadone significantly depressed late alcohol elimination.