Salhab, Hassan (2021) Potential assessment of CYP450s and UGTs inhibition by salicylic acid in rat and human supersomes 'in vitro'. (PhD thesis), Kingston University, .
Abstract
Background: Inhibition of cytochrome P450 (CYP) and UGTs enzyme activity can result in alteration in the pharmacokinetic parameters of a drug and lead to drug-drug interactions. In recent decades, acetyl salicylic acid has gained a lot of attention, mainly in the prevention of colorectal cancer (CRC). The purpose of this research was to determine the in vitro in hibitory effect of salicylic acid on CYP2C11 and CYP2E1 enzyme activities in rat liver microsomes and UGT2B17 enzyme activities in human supersomes using HPLC analysis. Methods: In chapter two, a testosterone and 16α-hydroxytestosterone (CYP2C11) assay, and in chapter three, a chlorzoxazone and 6-hydroxychlorzoxazone (CYP2E1) assay were developed on a reversed phase C18column (SUPELCO 25cm×4.6mm×5μm) using a low-pressure isocratic elution system. In chapter four, a testosterone, and testosterone glucuronide (UGT2B17) assay was developed on a reversed phase C18column (SUPELCO 25cm×4.6mm×5μm) using a low-pressure gradient elution system. Results: Substrates and metabolites for three assays showed good linearity (R2>0.99), good reproducibility, acceptable recovery, and accuracy (80%-120%), intra-and inter-day precision (<15%) and were stable for three days. Substrates and metabolites for all assays demonstrated low detection (<10μM), and quantitation limits (<20μM). Our inhibition studies showed that salicylic acid acts reversibly as a non-competitive (weak) inhibitor with Ki=84.582±2.67μM (IC50) =82.70±2.67μM for the CYP2C11 assay, and a mixed inhibitor (competitive and non-competitive) with Ki=83.56±2.730μM (IC50) =167.12±5.460μM for the CYP2E1 assay. Moreover, salicylic acid uncompetitively inhibited UGT2B17 enzyme activity. Conclusion: In conclusion, salicylic acid has both a low and high potential to cause toxicity and drug-drug interactions with drugs that are substrates for CYP2E1 in rats. Also, salicylic acid has a low potential to cause toxicity and drug-drug interactions with drugs that are substrates for CYP2C11 in rats and a negligible effect for UGT2B17 in humans.
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