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

• Published in: British journal of clinical pharmacology Vol. 83; no. 6; pp. 1279 - 1286
• Main Authors: Sohn, Jin A, Kim, Han‐Suk, Oh, Jaeseong, Cho, Joo‐Youn, Yu, Kyung‐Sang, Lee, Juyoung, Shin, Seung Han, Lee, Jin A, Choi, Chang Won, Kim, Ee‐Kyung, Kim, Beyong Il, Park, Eun Ae
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01-06-2017
• Subjects: Aging - metabolism; Apnea - drug therapy; Bronchodilator Agents - blood; Bronchodilator Agents - therapeutic use; Bronchodilator Agents - urine; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1A2 - metabolism; cytochrome P450 1A2; drug monitoring; Female; Genotype; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Paediatric Clinical Pharmacology; pharmacokinetics; premature infants; theophylline; Theophylline - blood; Theophylline - therapeutic use; Theophylline - urine; Uric Acid - analogs & derivatives; Uric Acid - urine; Xanthines - urine; premature infants; pharmacokinetics; theophylline; cytochrome P450 1A2; drug monitoring
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13211

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.