The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug’s stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are unacceptable variation in the bioavailability and high investment costs. Furthermore, novel oral anticancer drugs are frequently associated with toxic effects including unacceptable gastrointestinal adverse effects. Therefore, compliance is often suboptimal, which may negatively influence treatment outcome.

Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement.

Recent advances in the understanding of molecular mechanisms of cancer have led to the development of novel compounds that target specific cancer pathways. These drugs encompass monoclonal antibodies and tyrosine and non-tyrosine kinase inhibitors, and have been approved by the FDA and the European Medicines Agency, among others, for cancer treatment. These agents are associated with several toxic effects including potentially unacceptable gastrointestinal adverse effects. Diarrhea and hepatotoxicity, the most common adverse events experienced with these treatments, can frequently lead to treatment discontinuation and consequently decreased cancer control. We review the incidence and clinical patterns of the gastrointestinal and hepatic toxic effects induced by the main molecular-targeted therapies and propose some hypotheses for the causes of each adverse event.

Drug Insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy

Each year, 16,000 patients receive whole organ transplants in the United States alone, and this number is expected to increase yearly (1) Because the 1-yr survival rate for most transplant recipients is approaching 80%‐90% and continues to improve annually, an increasing number of patients who received a transplant present for either elective or emergency nontransplant surgery (2‐ 4) Therefore, anesthesiologists and surgeons are often required to manage transplant recipients in hospitals that are not otherwise involved in transplantation procedures The general considerations related to any transplant recipient are the physiological and pharmacological problems of allograft denervation, the side effects of immunosuppression, the risk of infection, and the potential for rejection

Anesthetic and perioperative management of adult transplant recipients in nontransplant surgery.

We report the tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD [40- O -(2-hydroxyethyl)-rapamycin] and its metabolites in monkey lung transplant recipients as well as its interaction with cyclosporine as the Neoral formulation. After left unilateral lung transplantation, cynomolgus monkeys received by oral administration either 1) 1.5 mg/kg/day SDZ-RAD ( n = 4); 2) 100 mg/kg/day cyclosporine ( n = 4); 3) 0.3 mg/kg/day SDZ-RAD + 100 mg/kg/day cyclosporine ( n = 6); 4) 1.5 mg/kg/day SDZ-RAD + 50 mg/kg/day cyclosporine ( n = 5); or 5) SDZ-RAD and cyclosporine doses adjusted according to trough blood concentration measurements ( n = 6). At the end of the observation period (usually 29 days after transplantation), and 24 h after the last doses, tissue samples were collected and analyzed with HPLC/mass spectrometry. Gall bladder, pancreas, the transplant lung, cerebellum, kidneys, and spleen had the highest SDZ-RAD concentrations. Coadministration of cyclosporine increased SDZ-RAD concentrations in most tissues as well as tissue-to-blood distribution coefficients. In contrast, SDZ-RAD had only a small effect on cyclosporine blood and tissue concentrations. Rejection in lung grafts in monkeys treated with either of the cyclosporine/SDZ-RAD combinations was significantly less than in the monotherapy groups ( P r = −0.68; P n = 24), lymph nodes ( P = −0.58; P n = 24), thymus ( r = −0.63; P n = 23) and transplant lung tissue ( r = −0.58; P n = 24). We conclude that, in addition to the synergistic pharmacodynamic interaction, a pharmacokinetic interaction resulting in higher SDZ-RAD tissue concentrations contributed to the significantly better immunosuppressive efficacy when both drugs were combined compared with monotherapy.

Tissue Distribution and Clinical Monitoring of the Novel Macrolide Immunosuppressant SDZ-RAD and Its Metabolites in Monkey Lung Transplant Recipients: Interaction with Cyclosporine

Co-administration of the calcineurin inhibitor cyclosporine and the mTOR inhibitors sirolimus or everolimus increases the efficacy of immunosuppression after organ transplantation. However, clinical studies showed enhancement of cyclosporine toxicity. To characterize the biochemical mechanisms involved, we assessed the time-dependent effects of cyclosporine in combination with mTOR inhibitors on energy production (ex vivo (31)P-MRS), glucose metabolism (ex vivo (13)C-MRS), and reactive oxygen species (ROS) formation (using the fluorescent agent 2',7'-dichlorofluorescein diacetate) in perfused rat brain slices. Cyclosporine alone inhibited energy production (ATP: 75+/-9%), the Krebs cycle (4-(13)C-glutamate from 1-(13)C-glucose: 61+/-27%), and oxidative phosphorylation (NAD(+): 62+/-25%) after 4 h of perfusion. After 10 h, activation of anaerobic glycolysis (3-(13)C-lactate: 140+/-17%) compensated for inhibition of mitochondrial energy production and lowered the intracellular pH. ROS formation was increased after 4 h (285+/-55% of untreated control), but not after 10 h. mTOR inhibitors alone inhibited lactate production. When combined with cyclosporine, sirolimus enhanced cyclosporine-induced inhibition of energy metabolism (ATP: 64+/-9%) and ROS formation (367+/-46%). Most importantly, sirolimus inhibited cytosolic glycolysis and therefore compensation for cyclosporine-induced ATP reduction after 10 h. In contrast to sirolimus, everolimus antagonized cyclosporine-induced inhibition of mitochondrial energy metabolism (ATP: 91+/-7%) and ROS formation (170+/-49%). The antioxidant tocopherol antagonized all cyclosporine effects on cell metabolism. Cyclosporine time-dependently inhibited mitochondrial metabolism and increased ROS, followed by compensation involving anaerobic glycolysis. Everolimus antagonized cyclosporine-induced mitochondrial dysfunction, whereas sirolimus inhibited compensatory anaerobic glycolysis, thus enhancing cyclosporine's negative effects. ROS play the key role in mediating the negative effects of cyclosporine on cell energy metabolism.

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Alterations in glucose metabolism by cyclosporine in rat brain slices link to oxidative stress: interactions with mTOR inhibitors.

The immunosuppressive drugs rapamycin (Rap) and cyclosporine A (CsA) are used clinically to modify or abolish immune-mediated functions. This study examined the effect of orally administered regimens of Rap, CsA, and a combination of Rap/CsA on intestinal function in male New Zealand white rabbits. Animals received oral doses of CsA (15 mg/kg/body weight/day), low-dose (LD) and high-dose (HD) Rap (0.25 or 1 mg/kg/body wt/day, respectively), or Rap/CsA (0.25 and 5 mg/kg/body wt/day, or 0.5 and 5 mg/kg/body wt/day, respectively) for 20 days. We measured in vitro uptake of nutrients and permeability, and morphometric measurements in the jejunum and ileum were made. Animals receiving HD-Rap or HD-Rap/CsA had decreased food intake, body weight, and intestinal weight, when compared with LD-Rap, LD-Rap/CsA, CsA, or controls. The maximal transport rate (Vmax) for the active jejunal uptake of D-glucose was increased in HD-Rap and CsA, but not in the HD-Rap/CsA-treated animals. The jejunal Vmax of D-glucose in the LD-Rap- or -Rap/CsA-treated animals was no different from controls. In the HD-Rap- and HD-Rap/ CsA-treated animals, jejunal rates of uptake of stearic, linoleic, and linolenic acids were reduced when compared with controls. Jejunal and ileal permeability (as assessed by the passive uptake of L-glucose, tissue conductance, and mucosal-to-serosal flux of [3H]inulin) was increased in animals treated with HD-Rap or HD-Rap/CsA, when compared with CsA or controls. These parameters of permeability were no different at lower doses of Rap or Rap/CsA. The jejunal and ileal villous surface area was increased in CsA, but decreased in HD-Rap or HD-Rap/CsA animals. Thus, HD-Rap given alone or in combination with CsA reduced body weight gain, in part due to reduced food intake and malabsorption of lipids, which was due at least in part to reduced intestinal surface area. The relevance of these findings to patients undergoing chronic immunosuppressive drug therapy needs to be established.

Oral Administration of Rapamycin and Cyclosporine Differentially Alter Intestinal Function in Rabbits

In addition to developing effective medicines and vaccines, pandemic preparedness also comprises general health-related, behavioral, and psychological aspects related to being more resistant in the case of future pandemics. In the context of the 2019 coronavirus (COVID-19) pandemic, recent research revealed that reduced perceived immune fitness was the best predictor of reporting more frequent and more severe COVID-19 symptoms. Up until now (June 2022), during the COVID-19 pandemic, the majority of patients who have been hospitalized were characterized as being overweight. It is therefore essential to further evaluate the relationship between body mass index (BMI) and immune fitness. This was performed by analyzing pooled data from previously published studies, conducted among N = 8586 Dutch adults. It was hypothesized that attaining a normal, healthy body weight is associated with optimal perceived immune fitness. The analysis revealed that a deviation from normal weight (i.e., having a BMI outside the range of 18.5 to 24.9 kg/m2) was associated with significantly reduced perceived immune fitness, as assessed with the immune status questionnaire and a single item perceived immune fitness scale. The effects were significant for both underweight and overweight groups and most pronounced for the obese groups. The results suggest that attaining a normal, healthy body weight might significantly contribute to maintaining adequate perceived immune fitness. Therefore, attaining a normal body weight might be an essential component of pandemic preparedness and should be supported by creating awareness and promoting the importance of regular exercise and the consumption of healthy food.

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K. E. Mulder

Papers

Oral Administration of Rapamycin and Cyclosporine Differentially Alter Intestinal Function in Rabbits

Pandemic Preparedness: Maintaining Adequate Immune Fitness by Attaining a Normal, Healthy Body Weight

A healthier daily diet is associated with greater immune fitness

Test-retest reliability of single-item assessments of immune fitness, mood, and quality of life.

The relationship between immune fitness and saliva biomarkers of systemic inflammation