Rapid and sensitive analysis of polymorphisms from breastmilk shows that ibuprofen is safe during certain stages of breastfeeding

Ibuprofen is a commonly used analgesic and second therapeutic class prescribed at different stages of lactation (1). We previously published a study about 20 women who received a mean daily dose of 1.012 mg ( 96 mg) of ibuprofen to treat pain or inflammatory disorders (2). Ibuprofen milk concentrations were measured using high-performance liquid chromatography, and the mean concentration was 360 160 lg/L. The mean ibuprofen transfer infant dose was 68 (8-262) lg/kg/day and the relative infant dose was <0.38% (0.04–1.53) of the weight-adjusted maternal daily dose, which was equal to 0.2% of the paediatric dose. Our advice is that ibuprofen is safe in the post-partum and later post-partum periods because the relative infant dose is very low in colostrum or mature milk. When Townsend et al. studied ibuprofen transfer in colostrum and Rigourd et al. studied it in mature milk, the relative infant dose was always under 1% (2,3). Our current belief is that there are sufficient pharmacokinetic data to confirm that there is a very poor transfer of ibuprofen from the mother’s milk to the neonate. We have concluded that the use of ibuprofen is compatible with breastfeeding after the early post-partum stage and with prolonged breastfeeding (2). Codeine, like ibuprofen, is often used as antalgic during the post-partum period. However, recent data have shown that codeine could trigger serious adverse events, even neonatal death (3,4), during breastfeeding. In contrast, ibuprofen did not show any adverse events. Codeine is fully metabolised by cytochrome 2D6, while ibuprofen is partially metabolised by CY2C8 (5) and preferentially metabolised by CYP2C9 (6). We studied the cytochrome P450 enzymes involved in ibuprofen metabolism: CYP2C8 and CYP2C9. DNA was extracted from 13 frozen breastmilk samples in 1-mL aliquots, using the Qiagen Kit (QiaSymphony DSP DNA; Qiagen, Courtaboeuf France). All the DNA was amplified by screening with taqman technology for cytochrome P450 polymorphism. Genotype analysis was carried out for cytochromes CYP 2C8 and CYP2C9. All laboratory procedures were performed in accordance with the local ethics committee (CPP Ile de France) and pharmacogenetics standard operating laboratory procedures at Paris South University’s School of Medicine. The chi-square test was used to compare the genotype frequencies and the associations with CYP2C8 and CYP2C9. We obtained a sufficient concentration of good-quality DNA (Table 1). Allelic variants were present in the same proportion as in the Caucasian population. For every genetic polymorphism, the relative infant dose of ibuprofen was less than 1.56%. These polymorphisms determine the pharmacokinetics of ibuprofen. Interindividual variability in drug metabolism is a major cause of adverse drug effects, and in nonsteroidal anti-inflammatory drugs (NSAIDs), this variability is linked to polymorphisms in genes coding for drug-metabolising enzymes. Both CYP2C8 and CYP2C9 contribute equally to the metabolism of ibuprofen (7). The main CYP2C9 polymorphisms responsible for the decrease of the enzyme activity and low metabolism, and the fortunate reduction in the high ibuprofen blood concentration, are two allelic mutations, CYP2C9*2 and CYP2C9*3. Unlike morphine,