Age‐ and genotype‐dependent UGT2B7 and UGT2B17 proteomics data explain the inter‐individual variability in metabolism of codeine and MK‐7246

Abstract

Background and ObjectiveUGT abundance and activity are associated with age and genetic polymorphisms. The aims of this project were to apply our previously generated quantitative UGT proteomics data i) to predict the effect of UGT2B7 ontogeny on the pharmacokinetics (PK) of morphine (an active metabolite) in breastfed neonate of a codeine‐prescribed mother, and ii) to predict age‐ and genotype‐dependent variability in the PK of MK‐7246 (MK; a UGT2B17 substrate) using physiologically‐based PK (PBPK) modeling.MethodsFirst an adult PBPK model was constructed and validated against the observed PK data following single oral dose of codeine (30 mg) and MK (1 mg) using Simcyp simulator. The simulation trial size was consisted of 10 trials of 10 subjects. The predicted adult codeine and morphine concentrations were validated by comparing literature data from adults with different CYP2D6 genotypes (i.e., poor, extensive and ultra‐rapid metabolizers, PM, EM, UM, respectively) and in breast‐feeding mother. We then predicted PK of codeine and morphine in neonates by integrating average milk intake, steady‐state milk‐to‐plasma ratio (2.5) and UGT2B7 ontogeny data into the PBPK model. Likewise, disposition of MK was predicted in children (age 0–18) and subjects carrying UGT2B17*2/*2, *1/*2 vs. reference allele (*1/*1) by integrating UGT2B17 proteomics data in the liver and intestine into the model. The models were evaluated by visual predictive checks and by comparison of predicted (mean and 5–95 % confidence intervals (CIs)) data with the observed PK parameters.ResultsThe predicted codeine mean AUC (ng/ml.hr) values in CYP2D6 PM, EM and UM adults were 211, 194 and 180 vs. 180, 191, and 192 (observed1), respectively. Similarly, the predicted morphine AUC (ng/ml.hr) values after codeine dose in adults were 0 (PM), 9.5 (EM), and 17 (UM), which were within the range of the observed data1 (Fig 1A). The normal neonatal morphine levels were closely predicted, i.e., < 2 ng/ml; however, the reported toxic levels linked to death of a neonate2 were only predicted accurately (54 vs. 70 ng/ml) when UGT2B7 activity was limited or not considered in mother and neonates. The predicted MK AUC (ng/ml.hr) also correlate the observed values in the adults (61.3 vs. 61.7; 4.8 vs. 6.1; 3.6 vs. 2.5) in case of carriers of UGT2B17 *2*2 (deletion), *1*2 and wild type *1*1 alleles3 (Fig 1B). We then predicted that MK clearance could be highly variable across age, e.g., 2 (neonates) to 85 (adults) ml/min/kg in the *1*1 individuals.DiscussionAge‐ and genotype‐dependent UGT abundance data are useful in predicting inter‐individual variability in drug metabolism. Consideration of variability in UGT2B7 mediated morphine metabolism after its formation from codeine could predict morphine toxicity, which is not fully explained by CYP2D6 variability alone2. Unprecedented variability in UGT2B17 protein abundance and its higher protein abundance in the intestine could be associated with larger age‐ and genotype‐dependent PK of its substrates as demonstrated for MK‐7246.Support or Funding InformationNIH R01 HD081299This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.