Piecing together human adult comparative pharmacokinetic trials and rodent studies: What happens to drug clearance in obesity?

In many comparative trials examining the effects of adult obesity on pharmacokinetics of drugs, conclusions were made based on values that were either not adjusted to total body weight or adjusted to non-obese body mass (e.g., ideal or lean body weight). In many cases these values were higher in the obese subjects. We have reviewed the data from comparative human trials, and it is apparent that in examining clearance normalization to total body weight (as typically done in studies involving pediatric obese patients), the clearances are often reduced in the obese. We have also reviewed the results of experimental obese versus non-obese rodent models. Those studies have mostly found that the systemic exposures to the same dose per body weight are increased, with obesity-related decreases in clearance. Furthermore, the expression of a number of important drug metabolizing enzymes are reduced in the experimental obese state. There is also evidence that obesity causes increases in the measured mass of eliminating organs such as liver and kidney. Human clearance normalized to total body weight appears to better reflect the underlying changes reported in the expression of protein and functional activity of drug clearance mechanisms.

EFFECT OF OBESITY AND ROUX-EN-Y GASTRIC SURGERY ON OMEPRAZOLE PHARMACOKINETICS

Background: The prevalence of obesity is increasing globally. Objectives: To evaluate whether gastric bypass surgery modifies the bioavailability and pharmacokinetic (PK) parameters of Omeprazole. Setting: Hospital Clínico San Carlos, Madrid, Spain. Methods: Controlled, open-label, bioavailability clinical trial in patients undergoing Roux-en-Y gastric bypass (RYGB). Healthy patients with obesity (BMI>35) were included and assessed for Omeprazole PK before RYGB and after (1 and 6 months). PK sampling was done at baseline and several times up to 12 h after drug dosing. Pre- and post-surgery parameters were compared using paired ANOVA or Wilcoxon tests, and Control vs. Cases using ANOVA or Mann Whitney tests. Given the post-surgery change in body weight, parameters were corrected by dose/body-weight. Results: Fourteen Case and 24 Control subjects were recruited, 92% were women (N= 35/38). In patients who underwent RYGB, Cmax was significantly reduced at 1 and 6 months after surgery compared with pre-surgery values (p=0.001). Regarding the AUC, the values are lower at 1 and 6 months after surgery than at baseline (p<0.001).The drug clearance was also increased in the first month after surgery. No differences were found between patients 6 months after surgery and Controls. Cmax and AUC corrected by dose/body-weight were significantly different between the baseline surgery subjects and Controls. Conclusions: Omeprazole bioavailability is reduced in patients with obesity at 1 and 6 months after RYGB. However, Omeprazole PK parameters 6 months after RYGB are similar to control subjects, and thus no dose correction is required after RYGB for a given indication.

Chronic kidney disease as a risk factor for acute stroke

One of the most relevant issues of nephrology, neurology, and cardiology is the management and treatment of patients with chronic kidney disease and stroke. Patients with chronic kidney disease have a risk of both thrombotic complications and bleeding, and they have a high risk of both ischemic and hemorrhagic stroke. Chronic kidney disease significantly worsens the outcome of stroke by limiting the treatment due to reduced drug clearance and side effects. Hemodialysis which causes drastic hemodynamic and biochemical changes leads to the "stress" of the cerebral vascular system, increasing the risk of stroke; kidney transplantation reduces the risk of stroke due to functional recovery. Chronic kidney disease and stroke have significant socio-economic consequences. Patients with end-stage chronic kidney disease, as a rule, are not included in clinical trials; and stroke treatment tactics have not been developed for them. This review examines the interaction between kidneys and brain, the pathophysiology and epidemiology of stroke in all stages of chronic kidney disease, after kidney transplantation and discusses the management and treatment of chronic kidney disease patients with stroke.The investigation of the factors responsible for the high prevalence of brain lesions in chronic kidney disease will allow developing new treatment methods.

Combined Hemoperfusion and Continuous Veno-Venous Hemofiltration for Carbamazepine Intoxication

<b><i>Introduction:</i></b> Carbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment. <b><i>Methods:</i></b> The Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected. <b><i>Results:</i></b> Combined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ. <b><i>Conclusion:</i></b> The combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.

A Short Review on Nasal Drug Delivery System

Nasal drug delivery has received a great deal of attention as convenient, reliable and promising methods for the systemic administration of drug. It is especially for those molecules which are ineffective oraly and only effective if administration by injection. The nasal route of drug delivery has advantage over the other alternative system of drug administration. The present review is an attempt to provide some information concerning nasal drug delivery system such as limitation, advantage, mechanism drug absorption, anatomy and Physiology Nasal, factor affecting of nasal drug delivery, drug distribution and deposition, Challenges and oppurtunities for Nasal Delivery Systems1. These drug delivery system have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions2..

Polymer-Based Nanosystems—A Versatile Delivery Approach

Polymer-based nanoparticles of tailored size, morphology, and surface properties have attracted increasing attention as carriers for drugs, biomolecules, and genes. By protecting the payload from degradation and maintaining sustained and controlled release of the drug, polymeric nanoparticles can reduce drug clearance, increase their cargo’s stability and solubility, prolong its half-life, and ensure optimal concentration at the target site. The inherent immunomodulatory properties of specific polymer nanoparticles, coupled with their drug encapsulation ability, have raised particular interest in vaccine delivery. This paper aims to review current and emerging drug delivery applications of both branched and linear, natural, and synthetic polymer nanostructures, focusing on their role in vaccine development.

UGT1A1 regulatory variant with potential effect on efficacy of HIV and cancer drugs commonly prescribed in South Africa

Aim: Despite the high disease burden of human immunodeficiency virus (HIV) infection and colorectal cancer (CRC) in South Africa (SA), treatment-relevant pharmacogenetic variants are understudied. Materials & methods: Using publicly available genotype and gene expression data, a bioinformatic pipeline was developed to identify liver expression quantitative trait loci (eQTLs). Results: A novel cis-eQTL, rs28967009, was identified for UGT1A1, which is predicted to upregulate UGT1A1 expression thereby potentially affecting the metabolism of dolutegravir and irinotecan, which are extensively prescribed in SA for HIV and colorectal cancer treatment, respectively. Conclusion: As increased UGT1A1 expression could affect the clinical outcome of dolutegravir and irinotecan treatment by increasing drug clearance, patients with the rs28967009A variant may require increased drug doses to reach therapeutic levels or should be prescribed alternative drugs.

Alteration of the Pharmacokinetics of Theophylline by Paullinia cupana Kunth in Rats

Aims: Paullinia cupana Kunth has been popularly used to prepare different beverages by the Amazonian inhabitants for a long time ago mainly due to its stimulant properties. Although the utilization of this herbal drug has been increasing lately, little is known regarding the possibility of drug interactions. Therefore, this research tried to investigate the effects of the aqueous extract of P. cupana on the pharmacokinetics of theophylline (TPH), a CYP1A marker in rats. Methodology: The extract was prepared according to the popular recipe and subjects received different once daily doses of extract (vehicle, 82.1 mg/Kg and 821 mg/Kg) by oral gavage during two weeks. Non-compartimental analysis was carried out to obtain the pharmacokinetic parameters. Results: Animals treated with P. cupana (AUC: 1,197.2 ± 284.4 and 346.6 ± 37.0 µg.h/mL for 82.1 and 821 mg/Kg, respectively) had lower exposition to TPH than controls (3,539.48 ± 278.4 µg.h/mL). On the other hand, drug clearance was higher in treated subjects (2.44 ± 0.4 and 7.27 ± 0.7 L/h/kg for 82.1 and 821 mg/Kg, respectively) than controls (0.71 ± 0.0 L/h/kg). Conclusion: Therefore, the multiple oral administration of an aqueous extract of P. cupana caused a significant effect on the pharmacokinetics of TPH in rats.