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Therapeutic Drug Monitoring and Toxicology: Relevance of Measuring Metabolites

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Recent Advances in Therapeutic Drug Monitoring and Clinical Toxicology

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Abstract

Therapeutic drug monitoring (TDM) is a valuable tool that healthcare providers have employed to optimize therapeutic efficacy of drugs while also maintaining drug concentrations below toxic levels. Although TDM has predominantly focused on determining the level of the parent drug compound in order to guide the dosing regimen, it is important to consider that some drugs are inactive in their parental forms and only their metabolites have therapeutic applications. Moreover, some drug metabolites possess distinct toxicity profiles from the parental compounds which are important to consider when evaluating the toxicity of a drug as a whole. This chapter investigates the role of metabolites in the safety assessment of drugs that are subject to TDM, such as those with narrow therapeutic windows. Examples of TDM of metabolites and mechanisms involved in metabolite-induced drug toxicity are discussed, drawing from several examples of drugs that are used in the clinical setting. This chapter emphasizes the utility of TDM of metabolites, demonstrating how select drugs can be converted to reactive metabolites with toxicity potential, and these should be considered when evaluating the efficacy and toxicity of a drug. The impact of pharmacogenetics in drug metabolism and the potential impact on efficacy and safety of drugs subject to TDM are also discussed. Finally, a cost-benefit analysis is made to support the inclusion of metabolite determination in routine TDM practice toward optimization of drug therapy.

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Notes

  1. 1.

    While it is common to refer to this as phase one reaction, this is not an accurate description of the reactions that take place. Referring to this as phase I only suggests that they take place first and other reactions follow. However, it has been shown that the other kind of reaction in the liver, which is generally referred to as phase II, may actually take place before “phase I,” simultaneously with “phase I,” or may even be the only major reaction that the xenobiotic undergoes. Therefore, phase I reactions are more accurately and broadly referred to as oxidative metabolism because a vast majority of reactions that take place via this route are oxidative in nature, while phase II reactions are more accurately referred to as conjugative metabolism as the other chemical moieties are added (conjugated) to the parent compound or its oxidative metabolite to create a new form.

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Authors and Affiliations

  1. Regulatory Toxicologist, London, ON, Canada

    James Akingbasote & Sandra Szlapinski

  2. Nationwide Children’s Hospital, Columbus, OH, USA

    Elora Hilmas & Patrik Miller

  3. Central Ohio Poison Center, Nationwide Children’s Hospital, Columbus, OH, USA

    Natalie Rine

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  1. James Akingbasote
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  2. Sandra Szlapinski
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  1. Department of Medical Pharmacology, University of Ghana Medical School, Accra, Ghana

    Seth Kwabena Amponsah

  2. USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA

    Yashwant V. Pathak

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Akingbasote, J., Szlapinski, S., Hilmas, E., Miller, P., Rine, N. (2022). Therapeutic Drug Monitoring and Toxicology: Relevance of Measuring Metabolites. In: Amponsah, S.K., Pathak, Y.V. (eds) Recent Advances in Therapeutic Drug Monitoring and Clinical Toxicology. Springer, Cham. https://doi.org/10.1007/978-3-031-12398-6_13

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