Dihydrocodeine Overdoses in a Neonate and in a 14-year-old Girl Who Were Both Genotyped as Cytochrome P450 2D61/10-36: Comparing Developmental Ages and Drug Monitoring Data With the Results of Pharmacokinetic Modeling

• Published in: Therapeutic drug monitoring Vol. 40; no. 2; p. 162
• Main Authors: Shimizu, Makiko, Kondo, Tatsuki, Fukuoka, Tetsuya, Tanaka, Toshihiro, Yamazaki, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States 01.04.2018
• Subjects: Adolescent; Codeine - administration & dosage; Codeine - analogs & derivatives; Cytochrome P-450 CYP2D6 - genetics; Drug Monitoring - methods; Drug Overdose - genetics; Female; Genotype; Humans; Infant, Newborn; Male; Models, Biological
• ISSN: 1536-3694
• DOI: 10.1097/FTD.0000000000000482

A high activity of cytochrome P450 2D6 (CYP2D6) reportedly leads to toxicity of dihydrocodeine/codeine by increasing toxic potential of their metabolite dihydromorphine/morphine, which are further metabolized to highly active dihydromorphine 6-O-glucuronide and the less active morphine 3-O-glucorinide but rapidly excreted into urine as water-soluble forms. A case of acute respiratory depression after administration of prescribed dihydrocodeine phosphate (2.0 mg/d divided twice a day for 2 days) to a 1-month-old baby boy genotyped as CYP2D6*1/*10-*36 is described. The case is compared with that of a 14-year-old girl, also genotyped as CYP2D6*1/*10-*36, presenting in an agitated state after an overdose (37 mg) of dihydrocodeine phosphate taken as simultaneous ingestion of multiple over-the-counter tablets. In contrast to the rapid clearance of dihydrocodeine from blood in the 14-year-old girl (apparent half-life of 3 hours), the 1-month-old baby boy still had high serum concentrations of dihydrocodeine (400 nmol/L) and dihydromorphine (1.9 nmol/L) 21 hours after the last oral administration of dihydrocodeine-containing cough mixture. The rapid clearance in the 14-year-old girl was mainly attributed to dihydrocodeine glucuronidation and partly attributed to dihydromorphine formation, as determined by liquid chromatography-tandem mass spectrometry analyses. However, the conjugation ratios of dihydrocodeine and dihydromorphine in the neonate were low in comparison with those in the 14-year-old girl and with those measured in 3-, 6-, and 13-year-old control subjects, resulting from the poorly developed glucuronidation potential of the neonate. The current observations suggest that the CYP2D6*1/*10-*36 genotype seen in the 2 Japanese patients may not significantly contribute to the likelihood of dihydrocodeine overdose but highlight the importance of considering age when prescribing dihydrocodeine.