The fate of drugs in the body: The impact of drug transporters and metabolizing enzymes on the pharmacokinetics of opioids and other substrates

Opioids like morphine are commonly used to treat moderate or severe (cancer) pain. Importantly, the nonmedical use of prescription opioid analgesics can lead to opioid use disorder (OUD), which is associated with high morbidity and mortality rates. Of note, one can also initially become addicted to opioids without first being exposed to prescription opioids, through the use of illicitly obtained opioids. Opioid agonist treatment with methadone, buprenorphine(-naloxone), or slow-release morphine is the most common evidence-based treatment modality for individuals with OUD. Still, not all patients are successfully recruited or retained in these medication therapies. Thus, several countries, including the Netherlands, offer pharmaceutical-grade heroin (diacetylmorphine; diamorphine) as a maintenance treatment option for those individuals (heroin-assisted treatment or HAT). Interestingly, psychedelic substances, such as ibogaine, have been associated with the alleviation of several substance use disorders and may hold promise as potential treatments for OUD. Shifting from cancer-related analgesia and palliative care to pharmacological cancer treatment, we have also studied an inhibitor of poly(ADP-ribose) polymerases (PARPs) 1 and 2, two enzymes essential to normal DNA repair activities. PARP inhibitors have revolutionized the treatment of women with certain forms of advanced ovarian cancer. Presently, four PARP inhibitors are approved for clinical use, including niraparib, which is also currently being tested in multiple clinical trials for treatment of other types of cancer than ovarian, such as intracranial tumors. It is well established that (trans)membrane transporters play a role in drug disposition, therapeutic efficacy, and adverse drug reaction. Clinical-pharmacokinetic drug-drug interaction studies have also suggested that transporters often work together with drug-metabolizing enzymes in controlling drug absorption and elimination. Consequently, the effects of changes in transport activity due to environmental factors (e.g., drug interaction) or genetic variation should be considered. This is especially relevant when predicting potential changes in the systemic exposure of drugs, which can result in clinically relevant (pharmacodynamic) effects. In this dissertation, using various genetically modified mouse models, we investigated the impact of efflux (ABCB1 and ABCG2) and uptake transporters (OATP1A/1B/2B1) and cytochrome P450 3A (CYP3A) enzymes on the pharmacokinetics and tissue distribution of two opioids (morphine and heroin), the psychedelic compound ibogaine, and the PARP1/2 inhibitor niraparib, plus their relevant metabolites. Moreover, we further demonstrated the usefulness of knockout and humanized transgenic mouse models to investigate the pharmacological properties of the studied drug transporters and drug-metabolizing enzymes. All in all, we hope that the obtained knowledge from the studies described in this dissertation will prompt further (pre-)clinical research and help improve both the safety and efficacy profiles of the studied compounds, especially when considering a broader clinical application.