Twenty-eight drugs, including cephem
antibiotics and
anti-inflammatory agents currently used or considered potentially useful in
neonatal intensive care nurseries in Japan, were examined to determine their influence on
albumin and
bilirubin interaction by means of a
glucose oxidase -
peroxidase method, using an automated analyzer (Arrows) for unbound
bilirubin (U.B.). The apparent binding constant for drugs to the high-affinity site on
albumin (KD) was determined. Of cephem
antibiotics,
latamoxef sodium (LMOX) and
cefazolin sodium (CEZ) were found to displace
bilirubin from
albumin (KD = 5.9 x 10(3) M-1 and 4.5 x 10(3) M-1, respectively) as strongly as Na
salicylate (KD = 6.8 x 10(3) M-1). Mephenamate and
indomethacin, which are used for medical closure of
patent ductus arteriosus in premature infants, were also found to be stronger
bilirubin displacers (KD = 1.3 x 10(5) M-1 and 1.2 x 10(5) M-1, respectively) than
sulfisoxazole (KD = 1.6 x 10(4) M-1). Maximal displacement factors (
MDF's) were also estimated in reference to protein binding (%) and effective serum concentration (M) of each
drug in human adults. Of these drugs, mephenamate showed a higher risk of
bilirubin displacement (
MDF = 3.79) than
sulfisoxazole (
MDF = 2.58) and LMOX had a higher risk of displacement (
MDF = 1.97) than Na
salicylate (
MDF = 1.85). On the other hand,
indomethacin and CEZ showed minimal effects on displacement at therapeutic levels (
MDF = 1.03 and 1.00, respectively). At therapeutic serum levels, mephenamate and LMOX may possess the potential for displacing
bilirubin from
albumin and increasing the risk of
bilirubin encephalopathy, in a manner similar to
sulfisoxazole.