The effect of diabetes mellitus on pharmacokinetics, pharmacodynamics and adverse drug reactions of anticancer drugs

Abstract

Diabetes mellitus (DM) and cancer are global problems carrying huge human, social, and economic impact. Type 2 diabetes (T2DM) is associated with an increased risk for a number of cancers, including breast, pancreatic, and liver cancer. Moreover, adverse drug reactions are higher in paitents with cancer with T2DM compared to cancer patients without T2DM. Cellular mechanisms of hyperglycemia and chemotherapy efficacy may be different depending upon the particular cancer type and the condition of the patient. This review evaluates the effect of DM on the pharmacokinetic, pharmacodynamic, and adverse drug reactions of commonly used anticancer drugs such as cisplatin, methotrexate, paclitaxel, doxorubicin, and adriamycin in both clinical and animal models. A literature search was conducted in scientific databases including Web of Science, PubMed, Scopus, and Google Scholar including the relevant keywords. The results of the effectiveness of anticancer therapies in patients with DM are, however, inconsistent because DM can negativelyimpact multiple diverse entities including nerves and vascular structures, insulin-like growth factor 1, the function of the innate immune system, drug pharmacokinetics, the expression levels of hepatic CYP 450 , Mdr 1b and enzymes that then lead to drug toxicity. However, in a few circumstances, DM led to attenuation of the toxicity of anticancer drugs secondary to attenuation of the energy-dependent renal uptake process. Overall, the impact of DM on patients with cancer is variable because of the diverse types of cancers and the spectrum of anticancer drugs. With respect to the evidence for cancer involvement in DM pathophysiology and the response to anticancer treatment in patients with DM, many questions still remain and further clinical trials are needed.

Evaluation of important human CYP450 isoforms and P‐glycoprotein phenotype changes and genotype in type 2 diabetic patients, before and after intensifying treatment regimen using Geneva cocktail

“…Numerous studies have been conducted on the effects of diabetes on the pharmacodynamics and pharmacokinetics of drugs. It has been demonstrated that diabetes mellitus can affect the pharmacokinetics of various drugs by affecting: absorption, due to the changes in subcutaneous adipose blood flow, muscle blood flow, and gastric emptying; distribution, due to the non‐enzymatic glycation of albumin; biotransformation, due to the regulation of enzymes/transporters involved in drug biotransformation and excretion, due to nephropathy 27,28 …”

“…It has been demonstrated that diabetes mellitus can affect the pharmacokinetics of various drugs by affecting: absorption, due to the changes in subcutaneous adipose blood flow, muscle blood flow, and gastric emptying; distribution, due the non-enzymatic glycation of albumin; biotransformation, due to the regulation of enzymes/ transporters involved in drug biotransformation and excretion, due to nephropathy. 27,28 Moreover, chronic inflammatory diseases such as T2D can affect the isoenzymes of CYP450 and change patients' reactions to drugs. To optimize the use of drugs, we should improve our knowledge about the impact of T2D on the metabolism of drugs.…”

Weaker Response to XueBiJing Treatment in Severe Community-Acquired Pneumonia Patients With Higher Body Mass Index or Hyperglycemia: A Post Hoc Analysis of a Randomized Controlled Trial

“…Our study also suggested that compared with the non-hyperglycemia group, the 28-day mortality rate in the hyperglycemia group is high, and the duration of ICU stay is long. In distribution studies, the increased level of glycosylation of plasma proteins could reduce the binding of a number of drugs in the blood (Gwilt et al, 1991;Mashayekhi-Sardoo et al, 2019). Hyperglycemia may lead to a decrease in the effect of XueBiJing, so dosage adjustment is required.…”

Identification of candidate mediators of chemoresponse in breast cancer through therapy-driven selection of somatic variants

“…A more surprising over-represented pathway was type II diabetes (with CACNA1C from our prioritized gene list). Some have reported that diabetes is associated with relatively poor breast cancer chemotherapy responses [46,47]; therefore, a mechanistic link is plausible. Higher expression of CACNA1C, a subunit of the Cav1.2 voltage-gated calcium channel, has been associated with improved therapy response in B-cell lymphoma to a combination regimen including both doxorubicin and cyclophosphamide (closely related to the therapy in our study), although the authors concluded that CACNA1C impacted on response to the rituximab component of their combination [48].…”