Solanidine Metabolic Ratios Suggest Incomplete CYP2D6 Phenoconversion in Pediatric Patients
Presenter Status
Graduate Student
Abstract Type
Clinical Research
Primary Mentor or Principal Investigator
Laura Ramsey
Presentation Type
Poster
Start Date
19-5-2026 11:00 AM
End Date
19-5-2026 12:00 PM
Abstract Text
Background: CYP2D6 is a highly polymorphic enzyme metabolizing 25% of medications, including psychotropic drugs commonly prescribed to youth. Genetic variation in CYP2D6 produces distinct metabolizer phenotypes—poor (PM), intermediate (IM), normal (NM), and ultrarapid metabolizers (UM)—that influence treatment response and side effects. Strong CYP2D6 inhibitors cause phenoconversion, a phenomenon where the functional enzyme activity is reduced below genotype-predicted levels. Individuals who are not CYP2D6 PMs and taking a strong inhibitor are assumed to be phenoconverted to a PM, yet the extent of phenoconversion has not been assessed. For some CYP2D6 substrates, FDA labels recommend similar dose adjustments for CYP2D6 PMs and those taking strong CYP2D6 inhibitors.
Objectives/Goal: To evaluate the magnitude of phenoconversion across CYP2D6 phenotypes in youths taking psychotropic medications known to be strong CYP2D6 inhibitors using urinary and plasma metabolic ratios of solanidine (Sol), a dietary glycoalkaloid found in potatoes, and CYP2D6 substrate.
Methods/Design: Children and adolescents (≤18 years old) participating in clinical studies and undergoing psychotropic treatment were genotyped for CYP2D6. Plasma and urine samples were collected and analyzed using LC-MS/MS to quantify Sol and its primary metabolites (4-hydroxy-solanidine [OH-Sol], 3-4-seco-solanidine-3,4-dioic acid [SSDA]). Log-transformed metabolic ratios [Log(Sol/OH-Sol) and Log(Sol/SSDA)] were calculated for plasma and urine, respectively. In a subset of patients with multiple samples, within-patient repeated measures compared metabolite ratios at baseline to subsequent timepoints with strong CYP2D6 inhibitor exposure to quantify phenoconversion magnitude. Statistical analyses were conducted in R.
Results: We analyzed 448 samples (n=233 plasma, n=215 urine) from 142 participants (mean age: 15.3±2.5 years, 69% female). The cohort included 15 PMs, 50 IMs, 72 NMs, and 5 UMs. Fluoxetine was the most common strong inhibitor (n=82 individuals), followed by bupropion (n=12 individuals) or both (n=8 individuals). At baseline without inhibitor exposure, PMs demonstrated elevated metabolite ratios compared to all other phenotypes (mean plasma Log[Sol/OH-Sol]: PM 3.5 vs. IM -0.5, NM -0.8, UM -1.0; p< 0.001). With strong inhibitor exposure, IMs and NMs showed significantly higher ratio than baseline (plasma p< 0.001; urine p< 0.01) yet remained well below PM levels. PMs showed no significant difference with inhibitor exposure, consistent with minimal baseline CYP2D6 activity. Longitudinal analysis of 29 participants with pre/post-inhibitor samples confirmed these findings. IMs (n=14) and NMs (n=10) demonstrated significant within-patient increases (all p≤0.004), while PMs (n=3) showed no change. Analysis of fluoxetine-treated individuals (n=95) showed dose-dependent inhibition, with higher weight-adjusted doses (>0.37 mg/kg) producing greater ratio shifts in IMs and NMs (p< 0.01). Patients with low activity scores (0.25–0.5) did not reach PM-level ratios while taking a strong inhibitor (all p≤0.0003).
Conclusions: Strong CYP2D6 inhibitors caused IMs and NMs to have reduced CYP2D6 activity based on plasma and urine Sol metabolic ratios; however, IMs and NMs did not replicate PM profiles, suggesting they have residual enzyme activity. This contrasts with current guidelines that recommend classifying non-CYP2D6 PMs patients on strong inhibitors as PMs and suggests they may not require equivalent dose adjustments.
Solanidine Metabolic Ratios Suggest Incomplete CYP2D6 Phenoconversion in Pediatric Patients
Background: CYP2D6 is a highly polymorphic enzyme metabolizing 25% of medications, including psychotropic drugs commonly prescribed to youth. Genetic variation in CYP2D6 produces distinct metabolizer phenotypes—poor (PM), intermediate (IM), normal (NM), and ultrarapid metabolizers (UM)—that influence treatment response and side effects. Strong CYP2D6 inhibitors cause phenoconversion, a phenomenon where the functional enzyme activity is reduced below genotype-predicted levels. Individuals who are not CYP2D6 PMs and taking a strong inhibitor are assumed to be phenoconverted to a PM, yet the extent of phenoconversion has not been assessed. For some CYP2D6 substrates, FDA labels recommend similar dose adjustments for CYP2D6 PMs and those taking strong CYP2D6 inhibitors.
Objectives/Goal: To evaluate the magnitude of phenoconversion across CYP2D6 phenotypes in youths taking psychotropic medications known to be strong CYP2D6 inhibitors using urinary and plasma metabolic ratios of solanidine (Sol), a dietary glycoalkaloid found in potatoes, and CYP2D6 substrate.
Methods/Design: Children and adolescents (≤18 years old) participating in clinical studies and undergoing psychotropic treatment were genotyped for CYP2D6. Plasma and urine samples were collected and analyzed using LC-MS/MS to quantify Sol and its primary metabolites (4-hydroxy-solanidine [OH-Sol], 3-4-seco-solanidine-3,4-dioic acid [SSDA]). Log-transformed metabolic ratios [Log(Sol/OH-Sol) and Log(Sol/SSDA)] were calculated for plasma and urine, respectively. In a subset of patients with multiple samples, within-patient repeated measures compared metabolite ratios at baseline to subsequent timepoints with strong CYP2D6 inhibitor exposure to quantify phenoconversion magnitude. Statistical analyses were conducted in R.
Results: We analyzed 448 samples (n=233 plasma, n=215 urine) from 142 participants (mean age: 15.3±2.5 years, 69% female). The cohort included 15 PMs, 50 IMs, 72 NMs, and 5 UMs. Fluoxetine was the most common strong inhibitor (n=82 individuals), followed by bupropion (n=12 individuals) or both (n=8 individuals). At baseline without inhibitor exposure, PMs demonstrated elevated metabolite ratios compared to all other phenotypes (mean plasma Log[Sol/OH-Sol]: PM 3.5 vs. IM -0.5, NM -0.8, UM -1.0; p< 0.001). With strong inhibitor exposure, IMs and NMs showed significantly higher ratio than baseline (plasma p< 0.001; urine p< 0.01) yet remained well below PM levels. PMs showed no significant difference with inhibitor exposure, consistent with minimal baseline CYP2D6 activity. Longitudinal analysis of 29 participants with pre/post-inhibitor samples confirmed these findings. IMs (n=14) and NMs (n=10) demonstrated significant within-patient increases (all p≤0.004), while PMs (n=3) showed no change. Analysis of fluoxetine-treated individuals (n=95) showed dose-dependent inhibition, with higher weight-adjusted doses (>0.37 mg/kg) producing greater ratio shifts in IMs and NMs (p< 0.01). Patients with low activity scores (0.25–0.5) did not reach PM-level ratios while taking a strong inhibitor (all p≤0.0003).
Conclusions: Strong CYP2D6 inhibitors caused IMs and NMs to have reduced CYP2D6 activity based on plasma and urine Sol metabolic ratios; however, IMs and NMs did not replicate PM profiles, suggesting they have residual enzyme activity. This contrasts with current guidelines that recommend classifying non-CYP2D6 PMs patients on strong inhibitors as PMs and suggests they may not require equivalent dose adjustments.
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Poster Board Number: 11