This review underlines the need for a careful prescription of tramadol and tapentadol. Although both are widely prescribed synthetic opioid analgesics, their toxic effects and potential dependence are not completely understood yet. In particular, concerning tapentadol, further research is needed to better assess its toxic effects.
Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy.
We aimed to manipulate the metabolism of Saccharomyces cerevisiae to produce lactic acid and search for the potential influence of acid transport across the plasma membrane in this process. Saccharomyces cerevisiae W303-1A is able to use l-lactic acid but its production in our laboratory has not previously been detected. When the l-LDH gene from Lactobacillus casei was expressed in S. cerevisiae W303-1A and in the isogenic mutants jen1∆, ady2∆ and jen1∆ ady2∆, all strains were able to produce lactic acid, but higher titres were achieved in the mutant strains. In strains constitutively expressing both LDH and JEN1 or ADY2, a higher external lactic acid concentration was found when glucose was present in the medium, but when glucose was exhausted, its consumption was more pronounced. These results demonstrate that expression of monocarboxylate permeases influences lactic acid production. Ady2 has been previously characterized as an acetate permease but our results demonstrated its additional role in lactate uptake. Overall, we demonstrate that monocarboxylate transporters Jen1 and Ady2 are modulators of lactic acid production and may well be used to manipulate lactic acid export in yeast cells.
The multidrug resistance (MDR) phenotype, frequently observed during cancer treatment, is often associated with drug efflux pump activity. However, many other factors are also known to be involved. Cancer cells often rely on aerobic glycolysis for energy production; this is known as the "Warburg effect" and is used as a survival mechanism. Associated to this event, a reverse pH gradient across the cell membrane occurs, leading to cytosol alkalinization and extracellular acidification. In the present study, we investigated the role of different mechanisms involved in MDR, such as altered tumor microenvironment and energetic metabolism. The breast cancer cell line MCF-7, used as model, was exposed to two widely used antitumor drugs, paclitaxel (antimitotic agent) and doxorubicin (alkylating agent). Cancer pH regulation was shown to be crucial for malignant characteristics such as cell migration and drug resistance. Our results showed that a lower extracellular pH induced a higher migratory capacity and higher resistance to the studied chemotherapeutical compounds in MCF-7 cells. Besides the influence of the extracellular pH, the role of the tumor metabolism in the MDR phenotype was also investigated. Pre-treatment with different bioenergetic modulators led to cell ATP depletion and altered lactic acid production and glucose consumption, resulting in increased sensitivity to paclitaxel and doxorubicin. Overall, this study supports the potential use of compounds targeting cell metabolism and tumor microenvironment factors such as pH, as co-adjuvants in conventional chemotherapy.
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