Assessment of Mouse-Specific Pharmacokinetics in Kidneys Based on 131I Activity Measurements Using Micro-SPECT

Background In order to acquire accurate drug pharmacokinetic information, such as that required for tissue dosimetry, micro-SPECT must be quantitative and allow an accurate assessment of radioligand activity in the relevant tissue. This study investigates the feasibility of deriving accurate mouse-specific time-integrated drug pharmacokinetic data in mouse kidneys from activity measurements using micro-SPECT. Methods An animal experiment was done to evaluate the accuracy of 131I activity quantification in mouse kidneys using a micro-SPECT system against conventional ex vivo gamma counting (GC) in a NaI(Tl) detector. The imaging setting investigated was that of the mouse biodistribution of a 131I-labelled single-domain antibody fragment (sdAb) currently being investigated for targeted radionuclide therapy of HER2-expressing cancer. SPECT imaging of 131I 365-keV photons was done with a VECTor/CT system (MILabs, Netherlands) using a high-energy mouse collimator with 1.6-mm-diameter pinholes. For each activity quantification technique, the pharmacokinetic profile from approximately 1 to 73 h p.i. of the radioligand was derived and the time-integrated activity coefficient per gram of tissue (ã/M) was estimated. Additionally, SPECT activity recovery coefficients were determined in a phantom setting. Results SPECT activities underestimate the reference activities by an amount that is dependent on the 131I activity concentration in the kidney, and thus on the time point of the pharmacokinetic profile. This underestimation is around − 12% at 1.5 h (2.78 MBq.mL− 1 mean reference activity concentration), -13% at 6.6 h (143 kBq.mL− 1), -40% at 24 h (15 kBq.mL− 1) and − 46% at 73 h (5 kBq.mL− 1) p.i. The ã/M value estimated from SPECT activities is, nevertheless, within − 15% from the reference (GC) ã/M value. Furthermore, better quantitative accuracy (within 2% from GC) in the SPECT ã/M value is achieved when SPECT activities are compensated for partial recovery with a phantom-based correction factor. Conclusion The SPECT imaging system used, together with a robust activity quantification methodology, allows an accurate estimation of time-integrated pharmacokinetic information of the 131I-labelled sdAb in mouse kidneys. This opens the possibility to perform mouse-specific kidney-tissue dosimetry based on pharmacokinetic data acquired in vivo on the same mice used in nephrotoxicity studies.

Importance of Nanoparticles for the Delivery of Antiparkinsonian Drugs

Parkinson’s disease (PD) affects around ten million people worldwide and is considered the second most prevalent neurodegenerative disease after Alzheimer’s disease. In addition, there is a higher risk incidence in the elderly population. The main PD hallmarks include the loss of dopaminergic neurons and the development of Lewy bodies. Unfortunately, motor symptoms only start to appear when around 50–70% of dopaminergic neurons have already been lost. This particularly poses a huge challenge for early diagnosis and therapeutic effectiveness. Actually, pharmaceutical therapy is able to relief motor symptoms, but as the disease progresses motor complications and severe side-effects start to appear. In this review, we explore the research conducted so far in order to repurpose drugs for PD with the use of nanodelivery systems, alternative administration routes, and nanotheranostics. Overall, studies have demonstrated great potential for these nanosystems to target the brain, improve drug pharmacokinetic profile, and decrease side-effects.

In Silico Food-Drug Interaction: A Case Study of Eluxadoline and Fatty Meal

Food-drug interaction is an infrequently considered aspect in clinical practice. Usually, drugs are taken together with meals and what follows may adversely affect pharmacokinetic and pharmacodynamic properties, and hence, the therapeutic effects. In this study, a computational protocol was proposed to explain the different assimilations of two µ-receptors agonists, eluxadoline and loperamide, with a peculiar pharmacokinetic profile. Compared to loperamide, eluxadoline is absorbed less after the intake of a fatty meal, and the LogP values do not explain this event. Firstly, keeping in mind the different pH in the intestinal tract, the protonation states of both compounds were calculated. Then, all structures were subjected to a conformational search by using MonteCarlo and Molecular Dynamics methods, with solvation terms mimicking the water and weak polar solvent (octanol). Both computational results showed that eluxadoline has less conformational freedom in octanol, unlike loperamide, which exhibits constant behavior in both solvents. Therefore, we hypothesize that fatty meal causes the “closure” of the eluxadoline molecule to prevent the exposure of the polar groups and their interaction with water, necessary for the drug absorption. Based on our results, this work could be a reasonable “case study”, useful for future investigation of the drug pharmacokinetic profile.