Josephine A. Procknal

Distribution of salicylate between neonatal and maternal serum at diffusion equilibrium.

The post‐distributive neonatal: maternal plasma salicylate concentration ratio following salicylate administration to the mother before delivery is appreciably higher than unity. The protein binding of salicylate and the albumin concentration in one such plasma pair were considerably higher in the neonatal than in the maternal plasma. Equilibrium dialysis of neonatal plasma or serum from 6 newborn infants against that of their mothers produced a neonatal: maternal salicylate concentration ratio above unity in alt cases even if the albumin concentration in the neonatal serum did not exceed that in the maternal serum. However, there was a strong correlation between the neonatal: maternal concentration ratios of salicylate and albumin. These observations demonstrate that conclusions concerning the distribution of a drug across the placenta in relation to its plasma protein binding characteristics must be based on the results of binding studies witti plasma or serum from neonates and their mothers, and not from other adult subjects.

Fetal acquisition and neonatal elimination of a large amount of salicylate

The purpose of this study was to determine the amount of salicylate acquired by a newborn infant from a mother who took 6.5 gm of aspirin a day during her entire pregnancy, and to characterize the kinetics of salicylate elimination by the infant. This healthy female infant was born with a salicylic acid concentration of 25 mg/100 ml plasma and 75 mg/kg body weight. The drug was eliminated during the first 5 days of life, primarily in the form of salicyluric acid. Salicylate elimination was relatively slower than in normal adults, but more rapid than in newborn infants of mothers who had taken only one small dose of aspirin shortly before delivery. The apparent in vivo KM and Vmax for salicylurate formation, on a body weight basis, were at the adult level. The slower elimination of salicylate (relative to adults) by the infant was due to immaturity of the glucuronidation and renal excretory pathways.

Salicylate kinetics in old age

Salicylate kinetics were determined in 28 subjects 25 to 92 years old who received single, oral doses of sodium salicylate (1 gm/1.73 m2). The serum AUC∞ of total salicylate did not correlate with age. There was a weak positive correlation between the AUC∞ of free (unbound) drug and age, but there was no apparent difference between the AUC∞ values of the 15 women and 13 men. Seven of the 16 subjects > 70 years of age cleared salicylate at about the same rate as the younger subjects. A comparison of these seven subjects with the nine > 70 years old who were slow eliminators of salicylate revealed that the latter group consisted of more bedridden patients and that these patients had somewhat lower serum albumin concentrations, but they did not differ from the more rapid eliminators with respect to serum creatinine or urea nitrogen levels, SGOT, average age, female/male ratio, and average body weight. The serum protein binding of salicylate decreased with increasing age, apparently due mainly to decreasing serum albumin concentrations.

Effect of renal transplantation on protein binding of drugs in serum of donor and recipient.

Blood sampies were obtained periodically before and for about 3 mo after renal transplantationfrom a donor (mother) and a recipient (9‐yr‐old son with bilateral nephrectomy) for determination of serum protein binding of salicylate and sulfisoxazole. Ten days after the transplant, the recipient had an acute rejection episode which was treated successfully. The free fraction values of the drugs in serum of the recipient were considerably above normal before transplantation, decreased to normal within 2 days after transplantation, increased again several days before the rejection episode and remained elevated for about 50 days, and then returned to normal. Serum protein binding of the drugs in the serum of the donor was decreased for only a few days after transplantation and then returned to normal.

Relationship between saliva salicylate concentration and free or total salicylate concentration in serum of children with juvenile rheumatoid arthritis.

Our purpose was to determine the feasibility of using salicylate (SA) concentrations in saliva as an indirect measure of SA concentrations in serum of children with juvenile rheumatoid arthritis. Sixty‐four paired blood and saliva samples were obtained from 17 children, 4 to 17 yr of age (average, 9 yr), who were receiving aspirin every 8 hr. Serum total (free and bound) SA concentrations ranged from 5 to 36 mg/100 ml. The fraction of free (unbound) SA in serum, determined by equilibrium dialysis against an equal volume of buffer, rose with increasing total SA concentration. SA concentrations in saliva correlated strongly with both free and total SA concentrations in serum. The ratio of SA concentration in saliva to total SA concentration in serum rose with increasing total SA concentration in serum, whereas the relationship between SA concentration in saliva and free SA concentration in serum was essentially linear. However, there was considerable intrasubject variation of the saliva SA to serum free SA concentration ratio that could not be related to fluctuations of saliva pH. Therefore another analysis of the relationship was performed, using areas under the concentration–time curve during a dosing interval (AUCτ), which were determined from 0‐, 2‐, 4‐, and 8‐hr saliva SA and serum free SA concentrations of 12 children. These patients had serum SA concentrations at or near steady state and had provided all 4 pairs of blood and saliva samples during 1 dosing interval. The time‐average saliva SA and serum free SA concentrations calculated from the AUCτ values are strongly correlated (r = 0.944, p < 0.001). The mean saliva SA to serum free SA concentration ratio determined from these data is 0.637. This ratio varied appreciably between patients (coefficient of variation, 24%; range of ratio values, 0.358 to 0.892), which limits the usefulness of salivary SA determinations as a noninvasive indirect method for monitoring serum free SA concentrations in children with juvenile rheumatoid arthritis.