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

Abstract

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.

Drug choice to lowering risk contiguity with Morbus Hansen disease: A review article

“…After being followed for three years, the Morbus Hansen incidence rate in the blanket group was significantly lower than the control group, but there was no significant difference between the contact group and the control group). Rifampin administration in the blanket group was effective in preventing Hansen's Morbus with the effectiveness of 75% [30].…”

“…This intervention was found to be most effective in the contact group of female patients, especially in neighbors and social contacts, where a trend towards an increased risk of Morbus Hansen transmission was obtained, followed by an increase in the effectiveness of a single dose of rifampin. In addition, there were also indications of an increase in the effectiveness of single-dose rifampicin in the contact group in patients who were included in the cluster of two or more Morbus Hansen patients at the time of the intervention [30].…”

“…Based on an analysis of costs, the combined expenditures between Morbus Hansen treatment with standard MDT (Multidrug Therapy) regimens and chemoprophylaxis with rifampin were more effective than treatment expenditures. Morbus Hansen with standard MDT alone without prophylaxis [30]. Another study by Bakker and friends was carried out on five islands in Indonesia that are endemic to Morbus Hansen.…”

Drug-disease interaction: Clinical consequences of inflammation on drugs action and disposition

“…Adipose is an active endocrine and paracrine tissue which releases adipokines, pro-inflammatory cytokines as well as NO (124). Increased plasma CRP concentrations and elevated inflammatory markers have been illustrated in obese patients, resulting in CYP downregulation (125). In addition to the changes in metabolizing enzymes, obesity is often associated with hyperlipidemia, leading to a higher concentration of lipoproteins.…”

Obesity-related genomic instability and altered xenobiotic metabolism: possible consequences for cancer risk and chemotherapy

“…Overall, current literature explicitly aiming at metabolic enzymes in humans is limited to only a few cytochrome P450 enzymes. However, some additional published studies which used probe drugs to investigate drug clearance are reviewed elsewhere (see Refs 75 , 76 ). Drug clearance is influenced by alterations in expression/activity of drug metabolising enzymes, but also by other factors such as distribution within the body or blood flow, and therefore might not enable a direct conclusion regarding expression or activity of metabolic enzymes.…”