This article reports on the development of UDP-glucuronosyltransferase 1A9 (UGT1A9) in neonatal and pediatric liver. The substrate 4-methylumbelliferone (4MU) with specific inhibition by niflumic acid was used to define specific UGT1A9 activity. Subsequently, in silico pharmacokinetic (PK) and physiology-based pharmacokinetic (PBPK) modeling was used to determine UGT1A9 maturation and hepatic clearance. Modeled maximal enzyme activity was 27.9 nmol.min(-1) . mg protein(-1) at 4 months of age, which had high concordance with the average V-max in 45 individual adult (>20 years) livers of 29.0 nmol . min(-1) . mg protein(-1). The activity of UGT1A9 ranged 7.5-fold in the adult population (4.1-54.5 nmol . min(-1) . mg protein(-1)). Expression of UGT1A9 correlated with age only in children younger than 1 year (Spearman r = 0.70). Activity correlated with expression up to 18 years of age (Spearman r = 0.76). Furthermore, scaling intrinsic hepatic clearance of 4MU with an allometric PK model yielded a high clearance at birth and then fell to adult levels (1.3 l . h(-1) . kg(-1) at 18.1 years for well stirred or 1.4 l . h(-1) . kg(-1) at 18.7 years for parallel tube). The Simcyp PBPK models did not converge but showed an increase in clearance at under 1 year of age and then decreased to adult levels at approximately 20 years of age. Allometric scaling may be more accurate in cases of high-extraction drugs. Enzyme activities or hepatic clearances did not differ with gender or ethnicity. The UGT1A9 isoform has higher normalized clearance for 4MU at young ages, which may explain how other UGT1A9 substrates, such as propofol, have higher clearances in children than in adults.
AB -This article reports on the development of UDP-glucuronosyltransferase 1A9 (UGT1A9) in neonatal and pediatric liver. The substrate 4-methylumbelliferone (4MU) with specific inhibition by niflumic acid was used to define specific UGT1A9 activity. Subsequently, in silico pharmacokinetic (PK) and physiology-based pharmacokinetic (PBPK) modeling was used to determine UGT1A9 maturation and hepatic clearance. Modeled maximal enzyme activity was 27.9 nmol.min(-1) . mg protein(-1) at 4 months of age, which had high concordance with the average V-max in 45 individual adult (>20 years) livers of 29.0 nmol . min(-1) . mg protein(-1). The activity of UGT1A9 ranged 7.5-fold in the adult population (4.1-54.5 nmol . min(-1) . mg protein(-1)). Expression of UGT1A9 correlated with age only in children younger than 1 year (Spearman r = 0.70). Activity correlated with expression up to 18 years of age (Spearman r = 0.76). Furthermore, scaling intrinsic hepatic clearance of 4MU with an allometric PK model yielded a high clearance at birth and then fell to adult levels (1.3 l . h(-1) . kg(-1) at 18.1 years for well stirred or 1.4 l . h(-1) . kg(-1) at 18.7 years for parallel tube). The Simcyp PBPK models did not converge but showed an increase in clearance at under 1 year of age and then decreased to adult levels at approximately 20 years of age. Allometric scaling may be more accurate in cases of high-extraction drugs. Enzyme activities or hepatic clearances did not differ with gender or ethnicity. The UGT1A9 isoform has higher normalized clearance for 4MU at young ages, which may explain how other UGT1A9 substrates, such as propofol, have higher clearances in children than in adults.
U2 - 10.1124/dmd.111.043752 DO - 10.1124/dmd.111.043752 M1 - Article JO - Drug Metabolism and Disposition JF - Drug Metabolism and Disposition SN - 0090-9556 IS - 7 VL - 40 SP - 1321 EP - 1327 ER -