RESUMO
The emergence of multidrug-resistant tuberculosis (MDR-TB) has led to a renewed interest in the use of second-line antibiotic agents. Unfortunately, there are currently dearths of information, data, and computational models that can be used to help design rational regimens for administration of these drugs. To help fill this knowledge gap, an exploratory physiologically based pharmacokinetic (PBPK) model, supported by targeted experimental data, was developed to predict the absorption, distribution, metabolism, and excretion (ADME) of the second-line agent capreomycin, a cyclic peptide antibiotic often grouped with the aminoglycoside antibiotics. To account for interindividual variability, Bayesian inference and Monte Carlo methods were used for model calibration, validation, and testing. Along with the predictive PBPK model, the first for an antituberculosis agent, this study provides estimates of various key pharmacokinetic parameter distributions and supports a hypothesized mechanism for capreomycin transport into the kidney.
Assuntos
Antituberculosos/farmacocinética , Capreomicina/farmacocinética , Modelos Biológicos , Animais , Antituberculosos/administração & dosagem , Teorema de Bayes , Transporte Biológico , Capreomicina/administração & dosagem , Simulação por Computador , Feminino , Humanos , Rim/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Método de Monte Carlo , Distribuição TecidualRESUMO
A method has been developed to track controlled drug release and transport in the brain. This method entails the use of a polymeric implant to release, over time, a paramagnetically labelled compound into the brain. Magnetic resonance imaging is used to determine the evolving concentration distribution. This method is well suited to other types of intracranial drug delivery systems as well as to track transport in other organs of the body.
Assuntos
Encéfalo/metabolismo , Gadolínio/farmacocinética , Imageamento por Ressonância Magnética , Compostos Organometálicos/farmacocinética , Ácido Pentético/farmacocinética , Ágar , Animais , Meios de Contraste , Preparações de Ação Retardada , Difusão , Implantes de Medicamento , Gadolínio/administração & dosagem , Gadolínio/química , Gadolínio DTPA , Técnicas In Vitro , Modelos Químicos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Ácido Pentético/administração & dosagem , Ácido Pentético/química , Polímeros , CoelhosRESUMO
Longitudinal mixing in the conducting airways of eight intubated anesthetized beagles (10.8 +/- 0.9 kg) was studied at functional residual capacity in the presence of forced sinusoidal flow oscillations and in the absence of fresh air bias flow. The ranges of oscillation conditions were: frequencies, f, from 3 to 18 Hz and minute volumes, Vosc, from 50 to 150 ml/sec, corresponding to tidal volumes, Vosc/f, from 0.3 to 4.5 ml/kg body mass. Oscillations were imposed during a breath holding interval incorporated into a modified single-breath nitrogen (N2) washout maneuver. The expired N2 fraction curves were analyzed with a Fickian diffusion model by adjusting the value of a global mixing parameter, (DA2), to achieve an optimal fit of the model to the data. The mixing parameter was an increasing function of minute volume and a decreasing function of frequency, which is well represented by the equation: (DA2) = 2.72 Vosc 1.74 f-1.57 By comparison to available theory and previous measurements in physical systems, this formula implies that Taylor-type dispersion is the dominant mixing mechanism in the conducting airways. Also, the diffusion model predicted, and the data verified, the existence of a mouth-ward 'diffusion flow' during breath holding. This effect, caused by the non-uniform nature of the summed airway cross-section, is directly correlated with the value of (DA2).