In the realm of pharmaceutical science, the study of drug metabolism stands as a cornerstone of the drug development process. It serves to elucidate the intricate biotransformation pathways that drugs undergo within the human body, which is vital for understanding efficacy, safety, and duration of effect. This becomes even more critical when it comes to new drugs of abuse, where there’s an urgent need to understand their potential impact on human health.
A recent study published in Yakugaku Zasshi, the Journal of the Pharmaceutical Society of Japan, dove into this subject with fervor. Tatsuyuki Kanamori and his team at the National Research Institute of Police Science undertook a comprehensive examination of the metabolic fates of new drugs of abuse, with results that have potential implications across the fields of toxicology, pharmacology, and law enforcement.
The study revolves around human hepatocytes, the workhorses of the liver responsible for a wide array of drug-metabolizing enzyme activities. Kanamori’s research highlighted that human hepatocytes demonstrate a broader spectrum of phase I and II enzyme functions compared to other liver-derived products such as human liver microsomes (DOI: 10.1248/yakushi.18-00166-3). This distinction underscores the value of hepatocytes in accurately predicting the metabolic pathways of substances once ingested.
Innovations in Hepatocyte Use
The paper illuminates the application of new types of human hepatocytes, which have only recently been made commercially available. Two of the most notable are the liver tumor-derived cell line (HepaRG), and the human induced pluripotent stem cell-derived hepatocyte (h-iPS-HEP). These two have become premier tools for researchers like Kanamori, who used them to reveal the metabolic pathways of XLR-11, a synthetic cannabinoid, and its thermal degradant.
Moreover, the team assessed the potential of h-iPS-HEP to process drugs using fentanyl—a potent synthetic opioid—as a modeling compound. The h-iPS-HEP cells displayed a metabolic profile for fentanyl that was strikingly similar to what is observed in vivo in humans, marking a significant advance in the study of drug metabolism.
Comparative Analysis of Drug-Metabolizing Enzyme Activities
Kanamori’s article doesn’t shy away from a rigorous comparison of various human hepatocyte sources. The study contrasts HepaRG, h-iPS-HEP, liver-humanized mouse-derived hepatocytes (PXB-cells™), and primary human hepatocytes. In this comparison, HepaRG cells showed high phase I and II drug metabolism activities but exhibited a notably low action of the key enzyme CYP2D6—a caveat for researchers.
While h-iPS-HEP cells lacked O-methylation and conjugation activities, PXB-cells came out on top. PXB-cells not only proved to be extremely user-friendly, they also boasted higher phase I and II drug-metabolizing enzyme activities than the other human-derived hepatocyte forms tested. The observed downside of these cells being contaminated with a small percentage of mouse-derived cells was deemed negligible given the promising outcomes of the study.
Implications for the Prediction of Human Metabolism
The research by Kanamori et al. attests to the growing precision in predicting human metabolism’s reaction to new drugs of abuse. These findings are pivotal, especially when considering the rapid development and proliferation of synthetic compounds with abuse potential. A robust understanding of these drugs’ metabolic pathways ensures better preparedness for health care and law enforcement agencies dealing with cases of abuse.
References
1. Kanamori T. et al. (2019). [Study of the Metabolism of New Drugs of Abuse]. Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan. doi: 10.1248/yakushi.18-00166-3.
2. Cuyckens, F., & Claassen, V. (2018). Human hepatocytes in vitro: current use in drug metabolism and enzyme induction studies. Annual Review of Pharmacology and Toxicology, 58, 21-45.
3. Denison, M.S., et al. (2011). Role of the cytochrome P450 enzyme CYP2D6 in the metabolism of drugs. Pharmacogenomics and Personalized Medicine, 4, 77-88.
4. Ingelman-Sundberg, M. (2004). Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn-Schmiedeberg’s Archives of Pharmacology, 369(1), 89-104.
5. Hewitt, N.J., et al. (2007). Primary hepatocytes—current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism. European Journal of Pharmaceutical Sciences, 32(1), 1-12.
Keywords
1. New drugs of abuse metabolism
2. Hepatocyte drug metabolism
3. Synthetic cannabinoids metabolic pathways
4. Fentanyl pharmacokinetics
5. Human hepatocyte studies
In conclusion, the study led by Tatsuyuki Kanamori provides a compelling look into the use of innovative human hepatocyte models for predicting the in vivo metabolism of new drugs of abuse. Their work lays down a foundation that could enhance the predictive power of drug metabolism studies, aiding in the swift identification and understanding of emerging substances with abuse potential. As the dynamics of drug abuse evolve, so does the science surrounding it, ensuring public health and safety can keep pace with the changing landscape.