Pharmacokinetic Considerations in Geriatric Medication

Aging have an impact on the pharmacokinetic and pharmacodynamic characteristics of drugs, resulting in clinically relevant safety and efficacy consequences. There appear to be a rise in gastrointestinal (GI) problems with age, and certain slight variations in the GI tract have been noted. Nevertheless, insufficient studies have been done on the impact of aging on the expression and activity of these GI transporters. Aging is associated with some reduction in first-pass metabolism that might be due to a decrease in liver mass and perfusion. Some medications with considerable first-pass metabolism, can have markedly enhanced bioavailability and, as a consequence bioavailability. Other high clearance (CL) medications have identical bioavailability in both young and old individuals. However, at the other hand, the first-pass activation of some prodrugs, may be slowed or decreased, leading to a reduction in bioavailability. Some drugs may have a low bioavailability when taken orally, benefitted from transdermal administration. There are still no specific age-related liver ailments, routine clinical tests of liver function do not vary substantially with age, the course, and outcome of some liver diseases can be affected by age. The characteristic of high or low extraction of a drug by the liver has been attributed to whether the metabolic clearance (CL) of a drug falls or remains unchanged with age. Reduction in renal function in elderly subjects, particularly glomerular filtration rate, affects the clearance of many drugs such as water-soluble antibiotics and nonsteroidal anti-inflammatory drugs. The therapeutic significance of these declines in renal excretion is governed by the drug's expected toxicity. Many drugs show their effects specially in old age patients in different manner and depend on age related factors. It must take appropriate precautions for administering of different drugs to the old age patients.

Glucagon Clearance is Preserved in Type 2 Diabetes

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity<i>. </i>Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T_½) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed.<i> </i>Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T_½. Individuals with obesity had neither a significantly decreased MCR, T_½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.

Glucagon Clearance is Preserved in Type 2 Diabetes

Hyperglucagonemia is a common observation in both obesity and type 2 diabetes, and the etiology is primarily thought to be hypersecretion of glucagon. We investigated whether altered elimination kinetics of glucagon could contribute to the hyperglucagonemia in type 2 diabetes and obesity<i>. </i>Individuals with type 2 diabetes and preserved kidney function (8 with and 8 without obesity) and matched control individuals (8 with and 8 without obesity) were recruited. Each participant underwent a 1-hour glucagon infusion (4 ng/kg/min), achieving steady-state plasma glucagon concentrations, followed by a 1-hour wash-out period. Plasma levels, the metabolic clearance rate (MCR), half-life (T_½) and volume of distribution of glucagon were evaluated and a pharmacokinetic model was constructed.<i> </i>Glucagon MCR and volume of distribution were significantly higher in the type 2 diabetes group compared to the control group, while no significant differences between the groups were found in glucagon T_½. Individuals with obesity had neither a significantly decreased MCR, T_½, nor volume of distribution of glucagon. In our pharmacokinetic model, glucagon MCR associated positively with fasting plasma glucose and negatively with body weight. In conclusion, our results suggest that impaired glucagon clearance is not a fundamental part of the hyperglucagonemia observed in obesity and type 2 diabetes.

The LOX-1 Receptor Ectopically Expressed in the Liver Alleviates Atherosclerosis by Clearing Ox-LDL in the Circulation

Objective: Ox-LDL is the core factor in the development of atherosclerosis. However, there are few therapyaimed at eliminating Ox-LDL. Here in this study, we investigate whether the expression of the lectin-like oxidized low density lipoprotein receptor (LOX-1) in the liver could lead to the phagocytosis and degradationof circulating Ox-LDL and prevent the deposition of oxidized lipids in the vascular wall, thereby alleviatingthe progression of atherosclerosis.Methods: ApoE-/- mice were randomly divided into three groups, the control group,the AAV8-TBG-eGFP group and AAV8-TBG-LOX-1 group. In the viral group, mice received an injection of AAV8-TBG-LOX-1 (1.16×1011 virus genome (vg)/animal/100 μl). The mice in the control group and the AAV8-TBG-eGFP group received the same amount of sterile saline and AAV8-TBG-eGFP injections. The expression of LOX-1 in the liver was detected by immunofluorescent, Western blot and immunohistochemistry. The safety was assessed by H&E staining and blood biochemical analyses. The function of LOX-1 in the liver was detected by the co- localization of LOX-1 and Dil-Ox-LDL under laser scanning confocal microscope. The Ox-LDL in plasma was detected by ELISA. Changes in blood lipids were assessed through blood biochemical analysis. The pro- gression of atherosclerotic lesions was detected by oil red O（ORO） staining. And the expression of VCAM- 1 in endothelial cells and the extent of macrophages in plaques were detected by immunofluorescence staining. The protein expression in liver was assessed by qRT-PCR and Western blot. Results: The expression of LOX-1 was stable in liver within 4 weeks. Ectopically expressed LOX-1 in the liver phagocytosed and degraded Ox-LDL and reduced Ox-LDL in circulating plasma but did not have a significant effect on blood lipid levels. After the expression of LOX-1 in liver, Ox-LDL can be cleared by the liver, thereby reducing VCAM-1 expression in vascular endothelium and migration of macrophages in plaques, and eventually alleviating the progression of atherosclerosis. Hepatic LOX-1 expression may facilitate the metabolic clearance of Ox-LDL by upregulating the expression of ABCG5/G8. Conclusions: Ectopic liver-specific expression of LOX-1 alleviates the progression of atherosclerosis by clearing Ox-LDL in circulation.

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.

The use of population modeling to optimize dosing of drugs used in anaesthesiology and intensive care

Effective pharmacotherapy requires an adequate drug dose that maximizes the effectiveness of therapy while minimizing adverse effects. Difficulties in dose selection arise from interindividual differences in drug pharmacokinetics and pharmacodynamics. Population modeling describes pharmacokinetic and pharmacodynamic processes in a population, taking into account the relationships in each patient, differences between patients, and the influence of covariates on drug pharmacokinetics and pharmacodynamics. The aim of this study was to develop population models for drugs used in anesthesiology and intensive care in special patient populations. The pharmacokinetics of sufentanil was described in infants and children after epidural and intravenous administration. The estimated absorption rate constant from the epidural space suggests slow systemic absorption of sufentanil and the possibility of flip-flop kinetics, which results in a slower decline in plasma concentrations at the end of drug administration compared with intravenous administration. The dependence of metabolic clearance on body weight and age was also demonstrated. A population model for the pharmacokinetics of tigecycline was developed for patients with sepsis or septic shock. No relationship between pharmacokinetic parameters and patient characteristics was detected, and the estimated interindividual and inter-occasion variability for clearance was small. This suggests that a universal dose is sufficient to achieve homogeneous drug exposure in critically ill patients. The pharmacokinetics of caspofungin was described in critically ill patients. The clearance and volume of central compartment showed systematic increase over time that was not explained by the covariates. The estimated increase in clearance values for three consecutive doses results in a clinically relevant reduction in drug exposure. The developed population models extend the knowledge of the pharmacokinetics of sufentanyl, tigecycline, and caspofungin. Simulations based on these models can aid the dosing decision-making process.

Postprandial Glycemic, Insulinemic, and Short-Chain Fatty Acids Responses Following the Consumption of Okara and Biovalorized Okara Incorporated Biscuits

Objectives Okara is a fiber-rich food processing by-product. However, it is underutilized as food due to its rapid putrefaction and poor sensorial properties. Valorization via fermentation (biovalorization) can alleviate its undesirable qualities while augmenting its soluble fiber content. The increase in soluble fiber may improve postprandial glycemic and insulinemic responses, potentially via generation of short-chain fatty acids (SCFAs) from colonic bacteria fermentation. This study aimed to assess the effect of consuming okara and biovalorized okara-containing biscuits on postprandial glucose, insulin and SCFAs responses in older Singaporeans. Methods Fifteen healthy middle-aged and older Singaporeans participated in a randomized controlled crossover trial. Subjects underwent a 4-hour mixed meal tolerance test with 100 g ingestion of 3 types of biscuits – control (C, no okara), biovalorised okara (RO) and autoclaved okara (AOK). RO and AOK biscuits were produced by 20% substitution of wheat flour with okara powder that was fermented with Rhizopus oligosporus (7% w/w) or autoclaved. The 4-hour incremental area under the curve (iAUC) of glucose, insulin and SCFAs (acetate, propionate and butyrate) were assessed. β-cell function was evaluated based on glucose stimulated insulin secretion, using a ratio of 4-hour AUC of insulin to glucose. Estimated insulin sensitivity (ISI) and metabolic clearance rate (MCR) were assessed with Stumvoll Index. Results Although no difference in glucose response was noted, RO showed significantly lower insulin iAUC (RO: 8931 ± 1058 mU/L × min, mean ± SE; C: 10271 ± 866 mU/L × min, p = 0.021) and improved β-cell function (p = 0.028) compared to C. AOK yielded significantly greater ISI and MCR compared to C (pISI = 0.016, pMCR = 0.009) while RO showed no difference against AOK or C. Significantly higher acetate and total SCFAs iAUC were evident for both RO and AOK relative to C (C vs RO: pacetate = 0.012, ptotal SCFA = 0.001; C vs AOK: pacetate = 0.015, ptotal SCFA = 0.001). AOK also had significantly greater propionate and butyrate iAUC compared to C (C vs AOK: pacetate = 0.002, pbutyrate = 0.001). Conclusions Consumption of okara and biovalorized okara-containing biscuits offers the benefit of attenuating postprandial insulinemic response possibly via SCFAs modulation. Funding Sources Singapore Ministry of Education

Toxicokinetic/Toxicodynamic Interaction Studies in Rats between the Drugs of Abuse γ-Hydroxybutyric Acid and Ketamine and Treatment Strategies for Overdose

γ-hydroxybutyric acid (GHB) is widely abused alone and in combination with other club drugs such as ketamine. GHB exhibits nonlinear toxicokinetics, characterized by saturable metabolism, saturable absorption and saturable renal reabsorption mediated by monocarboxylate transporters (MCTs). In this research, we characterized the effects of ketamine on GHB toxicokinetics/toxicodynamics (TK/TD) and evaluated the use of MCT inhibition and specific receptor antagonism as potential treatment strategies for GHB overdose in the presence of ketamine. Adult male Sprague-Dawley rats were administered GHB 600 mg/kg i.v. alone or with ketamine (6 mg/kg i.v. bolus plus 1 mg/kg/min i.v. infusion). Plasma and urine samples were collected and respiratory parameters (breathing frequency, tidal and minute volume) continuously monitored using whole-body plethysmography. Ketamine co-administration resulted in a significant decrease in GHB total and metabolic clearance, with renal clearance remaining unchanged. Ketamine prevented the compensatory increase in tidal volume produced by GHB, and this resulted in a significant decline in minute volume when compared to GHB alone. Sleep time and lethality were also increased after ketamine co-administration when compared to GHB. L-lactate and AR-C155858 (potent MCT inhibitor) treatment resulted in an increase in GHB renal and total clearance and improvement in respiratory depression. AR-C155858 administration also resulted in a significant decrease in GHB brain/plasma ratio. SCH50911 (GABAB receptor antagonist), but not naloxone, improved GHB-induced respiratory depression in the presence of ketamine. In conclusion, ketamine ingestion with GHB can result in significant TK/TD interactions. MCT inhibition and GABAB receptor antagonism can serve as potential treatment strategies for GHB overdose when it is co-ingested with ketamine.

Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.

The role of aldehyde oxidase in the metabolic clearance of substituted benzothiazoles

Introduction: A group of substituted benzothiazoles from a research project was found to have low microsomal clearance. However, these compounds had very high clearance in vivo. Experimental: In the present study, the clearance mechanism of two of the structural analogs, was investigated in vitro and in vivo. Results and Discussion: In vitro studies showed the formation of corresponding non-P450 dependent oxidative metabolites in S9, cytosol, and hepatocytes. The in vitro formation of these metabolites was observed in mouse, rat, non-human primates, and human. Dog did not form the corresponding metabolites in any of the matrices. Inhibition studies with S9 fraction and incubation with human recombinant aldehyde oxidase (AO) showed that the formation of the corresponding metabolites was AO dependent. To investigate the role of this pathway in vivo, mice were dosed with compound A and bile and plasma were analyzed. Most of the metabolites in bile contained the AO dependent oxidized benzothiazole moiety, indicating that metabolism involving AO was probably the main pathway for clearance. The same metabolites were also observed circulating in plasma. Mass spectrometric analysis of the metabolite showed that the oxidation was on the benzothiazole moiety, but the exact position could not be identified. Isolation of the metabolite of compound A and analysis by NMR confirmed the structure of the metabolite as C2 carbon oxidation of the thiazole ring resulting in carboxamide moiety. Further comparison of both metabolites with corresponding authentic standards confirmed the structures. Conclusion: To our knowledge, such an observation of in vitro and in vivo oxidation of substituted benzothiazole by AO has not been reported before. The results helped the medicinal chemists design compounds that avoid AO mediated metabolism and with better ADME property.