Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants

Abstract

Aims: The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants.

Methods: Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2 h, 4 h or 6 h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants.

Results: A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P < 0.001). Total, renal and nonrenal clearances of theophylline were 0.50 ± 0.29 ml kg^-1 min^-1 , 0.16 ± 0.06 ml kg^-1 min^-1 and 0.34 ± 0.28 ml kg^-1 min^-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance.

Conclusions: CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants.

Keywords: cytochrome P450 1A2; drug monitoring; pharmacokinetics; premature infants; theophylline.

Figure 1

The theophylline metabolic pathway. Molar percentages of the metabolites analyzed in our preterm infant group are expressed in parentheses. CYP1A2 is a major hepatic enzyme involved in the decomposition of approximately 90–95% of theophylline in human adults. CYP1A2 mainly catalyzes the conversion of theophylline to 1‐methylxanthine and 3‐methylxanthine (N‐demethylation), while CYP2E1 and CYP3A4 catalyze the conversion of theophylline to 1,3‐dimethyluric acid (8‐hydroxylation). 1‐Methylxanthine is oxidized very rapidly to 1‐methyluric acid by xanthine oxidase

Figure 2

Correlation between the serum and urine theophylline concentrations. There was a good correlation between the serum trough theophylline concentration and the theophylline concentration in spot urine. The association between serum and urine theophylline concentrations was assessed using simple linear regression analysis