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Nonopioid and Adjuvant Analgesic Agents
Published in Pamela E. Macintyre, Stephan A. Schug, Acute Pain Management, 2021
Pamela E. Macintyre, Stephan A. Schug
As with many of the older anticonvulsants, adverse effects are very common and potentially severe. The most frequently reported side effects are blurred vision, drowsiness, ataxia, vertigo, and nausea as well as leukocytosis and thrombocytopenia (Fricke-Galindo et al, 2018). Enzyme induction requires care with other medications. Other potentially adverse effects include blood dyscrasias (agranulocytosis or aplastic anemia), hepatic dysfunction, and skin reactions including the life-threatening Steven–Johnson syndrome.
General pharmacology
Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
Besides reducing the therapeutic efficacy of another drug, enzyme induction is sometimes responsible for worsening the side-effect profile of another drug. This is especially true of the drugs that produce toxic metabolites. For example, paracetamol, generally a safe drug is converted to a toxic metabolite called N-acetyl-p-benzoquinone by cytochrome P450 enzyme system. This metabolite is responsible for the hepatic necrosis seen in patients of paracetamol overdose. The risk of potentially life-threatening hepatic necrosis increases if the paracetamol overdose patient has concomitantly taken an enzyme inducer, e.g. alcohol.
Major prescribing pitfalls due to drug–drug interactions in the liver
Published in Hugh Mcgavock, Pitfalls in Prescribing and How to Avoid Them, 2017
A major risk of failing to understand enzyme induction is that the prescriber may attribute treatment failure to an inadequate dose, and increase the dose of the (right-hand column) drug to compensate. If the inducing (left-hand column) drug is then withdrawn, the new dose will be excessive, and will lead to toxicity.
In vitro cell-based models of drug-induced hepatotoxicity screening: progress and limitation
Published in Drug Metabolism Reviews, 2022
Maryam Mirahmad, Reyhaneh Sabourian, Mohammad Mahdavi, Bagher Larijani, Maliheh Safavi
Different systems using subcellular fractions of hepatic tissue like S9 fractions, human liver microsomes, recombinant CYP enzymes, and hepatocytes in conjugation with probe substrates could quantify CYP activity. Human liver microsomes, which are derived from lysed hepatic tissues, contain high levels of CYP as well as some phase II enzymes like UGTs. Accordingly, they are widely employed to evaluate drug biotransformation as well as the expression of CYP in the hepatic tissues (Walsky and Obach 2004). CYP enzyme induction usually results from stimulation of nuclear receptors that modulate the transcription of genes. Standard enzyme induction assay is to incubate drug candidates with hepatocytes and subsequently quantify changes in CYP enzyme function and/or mRNA expression using a probe substrate (Volpe and Balimane 2018). Following in vitro enzyme reaction, the production of metabolites or reduction of substrates can be measured by emitted fluorescence (fluorometry), light absorption (spectrophotometry), mass/charge ratio (MS), or light pulses generated by radioactive labels. The most versatile quantitative method for analyzing a substrate or its metabolites is the (LC-)MS approach. This has the benefit of allowing endpoint activity to be measured alongside cell viability in order to identify toxicity (Fowler and Zhang 2008).
A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats
Published in Xenobiotica, 2020
Priyanka Kulkarni, Ken Korzekwa, Swati Nagar
Drug transporters can complicate drug disposition as well as the safety and efficacy profiles of drugs (Giacomini et al., 2010; Shitara et al., 2006). Drug clearance and distribution can be impacted by active uptake of drugs into eliminating organs, as well as efflux out of the body, for example with biliary and renal excretion (Watanabe et al., 2009b). Uptake transporters can increase intracellular drug concentrations, thereby increasing the overall tissue distribution of the drug. Altered drug disposition in turn can affect the efficacy and toxicity profiles of drugs, and lead to drug-drug interactions (Hirano et al., 2006; Izumi et al., 2015). The organic anion transporting polypeptide (OATP) family of transporters has emerged as a determinant of drug disposition (Maeda et al., 2006; Shitara et al., 2013). These transporters catalyze the uptake of organic anions into the intestine and the liver, among other tissues. In the liver, predicted intracellular concentrations can be markedly higher than unbound plasma concentrations due to OATP activity (Hirano et al., 2004; Kulkarni et al., 2016; Menochet et al., 2012a,b). This may be especially important for drugs cleared primarily by the liver. In addition to increased clearance, higher intracellular concentrations can increase the likelihood of drug interactions due to enzyme induction or inhibition. For these reasons, it is important to understand and be able to predict the impact of transporters on intracellular and plasma drug disposition.
Allosteric activation of cytochrome P450 3A4 by efavirenz facilitates midazolam binding
Published in Xenobiotica, 2018
Tomohiko Ichikawa, Hirofumi Tsujino, Takahiro Miki, Masaya Kobayashi, Chiaki Matsubara, Sara Miyata, Taku Yamashita, Kohei Takeshita, Yasushige Yonezawa, Tadayuki Uno
CYP3A4 activators, including inducers, can reduce the therapeutic efficacy of co-medications or increase the risk of metabolite-induced toxicity. CYP induction requires a certain lag phase before an increase in enzyme activity is observed, attributable to the time required to increase the amount of enzyme available via transcription and translation (Pelkonen et al., 1998). In contrast, an increase in metabolic activity resulting from enzyme activation is instantaneous and, therefore, is not usually considered an effect of enzyme induction (Tang & Stearns, 2001). Although it is uncertain whether the heterotropic activation of CYP enzymes is clinically relevant in terms of the potential for DDIs, it is important to determine the effects of these phenomena on the binding affinity of midazolam to CYP3A4 in vitro. We show here that measuring Kd values by means of a spectral titration method is useful for characterising the type of binding and affinity for new drug candidates as well as their underlying CYP3A4-mediated DDI mechanisms (e.g. heterotropic activation and competitive inhibition).