Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

Aims

Evidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy.

Methods

Two paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step‐wise manner in nonmem® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin.

Results

A one compartment model with an age‐dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound.

Conclusions

The findings of our study suggest that the processes underlying changes in oral drug absorption after birth are drug‐independent and that the maturation function identified for paracetamol may be generally applicable to other BCS class I and II compounds for characterizing drug absorption in preterm as well as term neonates.     

2019—2021年青岛市精神卫生中心第二类精神药品使用情况分析

目的 统计青岛市精神卫生中心2019—2021年第二类精神药品使用情况并分析变化趋势,为临床合理用药提供参考。方法 采用回顾性分析方法统计青岛市精神卫生中心信息系统中2019年1月—2021年12月第二类精神药品的销售金额,并计算药品用药频度（DDDs）、限定日费用（DDC）以及药品排序比（B/A）。结果 2019—2021年,医院第二类精神药品销售金额呈逐年增长趋势,奥沙西泮片和佐匹克隆片的销售金额排序始终居于前2位;第二类精神药品的DDDs总体呈增长趋势,佐匹克隆片、氯硝西泮片、阿普唑仑片的DDDs排序始终居于前3位;第二类精神药品的DDC及排序基本稳定,其中奥沙西泮片、地西泮注射液的DDC较高,居于前2位;苯巴比妥片、地西泮片、劳拉西泮片（1 mg）、佐匹克隆片的B/A值接近于1.0。结论 青岛市精神卫生中心第二类精神药品的使用基本合理,后期仍需加强监督管理,以保证患者合理用药。     

Improved understanding of the effect of food on drug absorption and bioavailability for lipophilic compounds using an intestinal pig perfusion model

The purpose of this study was to investigate the relative importance of mechanisms behind the effect of food on the intestinal absorption and bioavailability for low solubility compounds by applying a porcine single-pass perfusion model. Nanoparticle suspensions of the model compounds, danazol and cyclosporine were perfused through the jejunum in isotonic fluid alone (control) and isotonic fluid with a P-glycoprotein (P-gp) inhibitor (verapamil) or dietary and endogenous lipids added. The drugs were also administered as saturated solutions in the isotonic fluid containing lipids. Administration of cyclosporine together with verapamil increased the absorption compared to the control (1.6 times) suggesting an effect on jejunal permeability. However, addition of dietary lipids to the media led to a 50% reduction in the absorption of cyclosporine indicating lack of major effects by P-gp inhibition by lipids in vivo. The absorption of danazol was increased (2.6 times) when administered as a nanosuspension in lipid containing media compared to the control, but decreased (60%) when administered as a solution in the same media. This shows how important dissolution of the drug nanoparticles is in drug absorption. The difference in the effect of lipids in the absorption of cyclosporine and danazol when administered as nanosuspensions may be due to different distribution to the colloidal structures present in the media, thereby rendering the drugs’ different diffusion rates in the perfused segment. In conclusion, solubilisation seems to be a more important factor than P-gp inhibition as an explanation for the food–drug interaction observed for several low solubility drugs. In addition, the partition into different colloidal structures seems to play a major role in the dissolution and absorption of poorly soluble drugs.     

Prevention and recovery of (μ-diethylentriamino)-chloro-palladium(II)-chloride induced inhibition of Na/K-ATPase by SH containing ligands – l-cysteine and glutathione

The effect of (mu(3)-diethylentriamino)-chloro-palladium(II)-chloride ([PdCl(dien)]Cl) on the activity of Na/K-ATPase from porcine cerebral cortex was studied in vitro, in the absence and presence of -SH containing ligands L-cysteine and glutathione (GSH). The aim of the study was to elucidate the mechanism of [PdCl(dien)](+) induced inhibition of the enzyme activity and to examine the ability of thiols to prevent and recover the inhibition. The coordinative interaction between [PdCl(dien)](+) and enzyme was verified by UV and (1)H NMR spectra. The semblance in the changes in absorption spectra of [PdCl(dien)](+) in the presence of Na/K-ATPase and thiols (L-cysteine and GSH) suggested that the complex ion interacts with enzymatic sulfhydryl groups. [PdCl(dien)](+) inhibited the enzyme activity in a dose-dependent manner. The Hill analysis of the inhibition curve yielded the half-maximum inhibitory activity value, IC(50)=1.21 x 10(-4)M, and Hill coefficient, n=0.7, suggesting the negative cooperation for binding of [PdCl(dien)](+) to the enzyme. Dependence of the initial reaction rate on the concentration of MgATP(2-) exhibited typical Michelis-Menten kinetics in the absence and presence of the inhibitor. Kinetic analysis showed that [PdCl(dien)](+) inhibited Na/K-ATPase by reducing the maximum reaction rate (V(max)), rather than changing the affinity to the substrate (K(m)). Kinetic parameters derived using Lineweaver-Burk transformation of experimental data indicated the non-competitive nature of Na/K-ATPase inhibition. The inhibitory constant, K(i)=1.05 x 10(-4)M, was determined from secondary replot of Lineweaver-Burk graph, and correlated with stability constants of [Pd(dien)(thiol)] complexes. 1 x 10(-3)M L-cysteine or GSH prevented the enzyme inhibition induced by Pd(II) complex cation when present below 1 x 10(-4)M. The both thiols completely reversed the inhibited activity in the concentration dependent manner, due to the complex formation with [PdCl(dien)](+).     

Effect of mitomycin-C on the bioavailability of the radiopharmaceutical (99m)technetium-phytic acid in mice: a model to evaluate the toxicological effect of a chemical drug.

The many desirable characteristics of technetium-99m ((99m)Tc) have stimulated the development of labelling techniques for different molecular and cellular structures. It is generally accepted that a variety of factors can alter the biodistribution of radiopharmaceuticals and one such factor is drug therapy. Because patients on chemotherapeutic treatment receive a radiopharmaceutical in a nuclear medicine procedure, we have studied in Balb/c mice the effect of mitomycin-C on the biodistribution of the radiopharmaceutical (99m)Tc-phytic acid ((99m)Tc-PHY) used in hepatic scintigraphy. Mitomycin-C is an antineoplastic agent obtained from Streptomyces caesptosus and is used on the treatment of disseminated adenocarcinoma of the stomach or pancreas. Three doses of mitomycin-C were administered via the ocular plexus into Balb/c mice. One hour after the last dose, (99m)Tc-PHY was administered and the animals were sacrificed. The organs were isolated, the radioactivity was determined in a well counter and the percentages of radioactivity in the organs were calculated. The results have shown that the percentage radioactivity has been increased in stomach, spleen, lung, thyroid and bone, decreased in pancreas and thymus and not altered in ovary, uterus, kidney, heart, liver and brain. The changes in the distribution of (99m)Tc-PHY may be the result of metabolic processes and/or therapeutic actions produced by the administration of mitomycin-C.     

The transillumination technique as a method for the assessment of spermatogenesis using medicinal plants: the effect of extracts of black maca (Lepidium meyenii) and camu camu (Myrciaria dubia) on stages of the spermatogenic cycle in male rats

Abstract

Transillumination technique for assessment of stages of spermatogenic cycle is a useful tool for toxicological studies. This study was designed to determine the effect of two medicinal plants on spermatogenesis in male rats using the transillumination technique. For this, the effect of the combination of a fruit with highest content of ascorbic acid (Myrciaria dubia, camu camu) and extract of black maca (Lepidium meyenii) on seminiferous tubule stages scored by transillumination on intact tubules in adult male rats was assessed. Animals were treated during seven days with vehicle, black maca, camu camu or a mixture of black maca?+?camu camu and assessed for daily sperm production (DSP), stages of spermatogenic cycle as well as antioxidant activity and levels of flavonoids and polyphenols. Black maca increased stages of spermiation (VII–VIII) and mitosis of germ cells (IX–XI), whereas camu camu increased stages of mitosis (IX–XI) and meiosis (XII). Mixture of maca?+?camu camu increased stages of spermiation, mitosis and meiosis. All treatments increased DSP (p?<?0.05) and epididymal sperm count (p?<?0.05). Total polyphenols, flavonoids levels and antioxidant activity were higher in camu camu (p?<?0.001) than in black maca. In conclusion, M. dubia (camu camu) has potential effects improving spermatogenesis and co-administered with maca increase stages of mitosis, meiosis and spermiation of the spermatogenic cycle as assessed by the transillumination technique. This technique is becoming increasingly a useful tool for assessment spermatogenesis.