Decreased serum protein binding of diazepam and its major metabolite in the neonate during the first postnatal week relate to increased free fatty acid levels.

Abstract

The protein binding of diazepam (D) and its major active metabolite N-desmethyl diazepam (DD) was investigated in vitro in the serum of 14 mothers at birth, 21 foetuses at birth, in 100 neonates between 1 and 11 days of age and in 16 control subjects. The free (unbound) fractions of D and DD in the foetus were similar to those in the controls, but lower than those in the mothers. During the first day of life the free fractions of D and DD doubled in the neonates and subsequently declined slowly to reach near control levels at 1 week of age.The sharp increase and slow decrease of the free fractions of D and DD during the first postnatal week was closely paralleled by sharply increasing and decreasing free fatty acid (FFA) concentrations. Bilirubin and albumin levels were of lower importance in regard to the protein binding of D and DD.These results indicate that the greatly increased FFA levels shortly after birth result in increased free fractions of D and DD. Because of the known immaturity of the neonatal hepatic elimination capacity, these elevated free fractions may result in elevated free concentrations of the two compounds, which may help to explain the adverse effects observed clinically in some D-exposed neonates.

Protein binding predictions in infants

“…For example, Nau et al reported that the elevations in free fatty acids shortly after birth result in increased free fractions of diazepam and its main metabolite 27 . Ehrnebo et al reported that hyperbilirubinemia reduced the binding of a number of acidic drugs 26 .…”

Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

“…These include the drug and its concentration, the presence of binding competitors, the type and quantity of plasma protein, and the proteins' affinity for the drug. Nau et al (7) observed a twofold increase in the free fraction of diazepam in the serum of neonates that accompanied marked increases in free fatty acids and bilirubin, competitors for albumin-binding sites. Albumin levels progressively rose during a 6-d postgestation monitoring period, but remained significantly lower than in adults.…”

“…Although therapeutic ranges for drug monitoring are frequently reported in terms of total drug concentration in blood or plasma, the unbound drug concentration provides a better index for monitoring highly-bound compounds. This is particularly true for patients for whom there are disease-or age-related alterations in plasma protein content or composition (4-6) Adverse effects of diazepam in newborns, for example, have been attributed to significant elevations in serum concentrations of unbound parent compound and N-desmethyldiazepam, its major active metabolite (7).…”

Plasma Protein Binding of Theophylline during Development in the Rabbit

“…Therefore, when the spe cific plasma protein binding percentage of a drug is altered by physiological [2] or patho logical [3][4][5] events, both the pharmacoki netic profile and the expected pharmacologi cal response may be affected. A few endoge nous compounds are known to interact with drug protein binding [6][7][8]. The free fraction plasma concentration should be monitored for compounds that are highly bound or have a narrow therapeutic range [9].…”