Analysis of The Trends in Drug Metabolism and Pharmacokinetics

Understanding DMPK properties is critical for drug development and precision medicine. Drug metabolizing enzymes and transporters play a very important role in the control of PK. Furthermore, transcriptional and post-transcriptional factors such as nuclear receptors and non-coding RNAs (ncRNAs) are critical in the regulation of PK and provide insight into the regulatory mechanisms addressing PK issues. These mechanism-driven PK studies can increase the success rate of drug development related to their efficacy and safety, and improve the rational use of drugs in clinical practice.

Drug-metabolizing enzymes mediate the metabolism of exogenous and endogenous substances. Most drugs lose their pharmacological activity mainly through metabolic transformation, producing metabolites with high water solubility, which are easily excreted from the body. Therefore, metabolic enzymes play an extremely important role in the control of drug PK. The biotransformation of xenobiotics by xenobiotic-metabolizing enzymes (XMEs) can be divided into phase I and phase II reactions. Advanced characterization of enzymes involved in drug metabolism in humans is urgently needed to help avoid serious adverse drug reactions. Progress is being made in understanding the role of drug-metabolizing enzymes in PK control, including individual isoforms of many enzymes, such as cytochrome P450 (CYP) and UGT, and their selective substrates, inducers, and inhibitors. This section also discusses other non-P450 oxidases and conjugating enzymes, as an increasing number of drugs are metabolized by these enzymes.

Understanding mechanism-based changes in enzyme activity is critical to improving the clinical use of drugs. Recent studies have shown that new chemicals and herbal products act as inducers or inhibitors of CYPs. For example, CYP7A1 is upregulated by an intestinal HIF-2α inhibitor called PT2385. The ketene intermediate of erlotinib can inactivate CYP3A4 and CYP3A5, resulting in liver damage. Due to the complexity of components in herbal extracts, herbal products usually exhibit different effects on the regulation of multiple enzymes. Sophora flavescens can inhibit the activities of CYP2B6, CYP2C8, CYP2C9 and CYP3A, while catalpol can inhibit the activities of CYP3A4, CYP2E1 and CYP2C9. Other regulators can also alter the expression of CYPs. For example, the tumor suppressor p53 can directly regulate Cyp2b10, thereby attenuating APAP-induced hepatotoxicity.

The contribution of non-P450 enzymes to drug metabolism can be substantial and affect overall drug development. Non-CYP enzymes can be divided into four main groups: namely, oxidizing, reducing, conjugating and hydrolyzing. Non-CYP oxidases include flavin-containing monooxygenase (FMO), monoamine oxidase (MAO), peroxidase, xanthine oxidase (XO), aldehyde oxidase (AO), alcohol dehydrogenase (ADH) and Aldehyde dehydrogenase (ALDH).

Little is known about the regulation of the content and activity of non-P450 oxidases. Recently, selective substrates and inhibitors of some non-P450 enzymes have been identified in natural products and other sources. FMOs are involved in the metabolism of various xenobiotics. Well-known FMO inhibitors include indole-3-carbinol and methimazole, and 2-mercaptobenzimidazole. MAO, divided into two distinct isoforms (MAO-A, MAO-B), is an enzyme involved in the catabolism of monoamines. Benextramine and its derivatives were identified as novel human monoamine oxidase inhibitors as drug candidates for the treatment of neurodegenerative diseases. UDP-glucuronosyltransferases (UGTs) are a family of endoplasmic reticulum-bound enzymes responsible for the process of glucuronidation, a major part of phase II metabolism. Human UGTs include 22 distinct functional enzymes grouped into four gene families: UGT1, UGT2, UGT3, and UGT8. The UGT1 and UGT2 families are mainly enzymes involved in drug glucuronidation, while the UGT3 and UGT8 families contribute little to drug metabolism.

The ADME process determines drug concentrations in blood and tissues, and subsequent pharmacological or toxicological effects. Both the intestine and the liver strictly regulate the entry of drugs into the blood circulation and are important organs that determine the bioavailability of orally administered drugs. Elimination of a drug or its active metabolite occurs by metabolism to an inactive metabolite and excretion, or by direct excretion of the drug or active metabolite in the kidneys. The transport proteins expressed in the intestine, liver, and kidney are involved in the absorption, distribution, and excretion of drugs, and are the main factors that determine the blood drug concentration and tissue concentration of drugs.

DMPK research is critical to understanding drug efficacy and safety. Comprehensive studies of drug-metabolizing enzymes and transporters underlying the ADME process and their mechanisms of transcriptional and post-transcriptional regulation provide a comprehensive understanding of individual differences in drug therapy. Future research in these areas will undoubtedly advance our understanding to better predict PK properties. With the application of sensitive and accurate analytical instruments and techniques, many new metabolic reactions and biotransformation pathways have been and will be discovered. In the future, it will be possible to more accurately predict drug metabolism and elucidate the metabolic mechanisms leading to adverse drug reactions and DDIs. Overall, DMPK research awaits further innovation and mechanistic studies, while DMPK remains a key component in drug development and is essential for the implementation of precision medicine.