Plasma concentrations of phenobarbital in mother and child after combined prenatal and postnatal administration for prophylaxis of hyperbilirubinemia.

Phenobarbital is known to reduce serum bilirubin concentration in the newborn infant, but optimal dosage is unknown. Ten pregnant women and their infants were given a standard regimen including prenatal maternal administration and postnatal administration to the infant during the first week of life. The plasma levels of phenobarbital in the infants were found to increase during the period of administration, and to remain high for many days beyond the period of hyperbilirubinemia. Optimal dose schedules for phenobarbital should be based both upon pharmacologic effects (including those other than bilirubin disposition) and upon the pharmacokinetic profile of the drug in the newborn infant.

Phenobarbital metabolism in adults and in newborn infants.

Two adult volunteers and four newborn infants were given a single dose of phenobarbital. The output in the urine o f unchanged phenobartital and of the two main metabolites p-hydroxy phenobarbital and conjugated p-hydroxy phenobarbital was followed during 8 days in the newborns and during 2 or 4 weeks in the adults. The plasma levels were also determined and some pharmacokinetic constants calculated. It was found that the newborn patients excreted unchanged phenobartibal and p-hydroxy phenobarbital in the same proportions relative to dose as did the adult volunteers, 2.e. 16--17% unchanged drug and 9--10% of the metabolite during the first 8 days after administration. On the other hand, there was a clear-cut age difference in output of conjugated metabolite where the newborns excreted only 5% of the given dose during the 8-day observation period. The corresponding value for the adults was 15%. It is concluded that a poor conjugating capacity in the newborn may not have any serious consequences with a drug like phenobarbital where major alternative routes of excretion exist (unchanged drug and unconjugated metabolite). The clinical significance of immature drug metabolites and of unchanged drug is taken into consideration.

Pharmacokinetic aspects of streptomycin treatment of neonatal septicemia.

Patients with suspected neonatal septicemia were treated with ampicillin, cloxacillin, and streptomycin. The plasma concentrations of streptomycin were followed. First, the levels were determined during a full dose interval (12 h) in 11 infants. The results were used for development of a routine system for monitoring the plasma levels in all streptomycin treated newborns. This system, the "3-point check", involved blood sampling at 1, 3, and 5 h after administration during every second dose interval. The results of this routine procedure were evaluated both in a retrospective and prospective study. The "3-point check" gave a sufficient description of the total exposure to streptomycin under routine clinical conditions and continuous information to the physician in charge of the patient about the drug level. In 9 cases of 50, the report from the laboratory resulted in dose change for correction of a too low or too high plasma concentration. The dosage used, 7.5 mg streptomycin intramuscularly every 12th hour, appeared to be satisfactory in most patients. Peak values rarely exceeded 30 microgram/ml and were usually lower than 25 microgram/ml. Almost half of the children had plasma levels below 5 microgram/ml at the end of the dose interval (after 12 h). Although the correlation between pharmacokinetics and clinical outcome is difficult to establish in neonatal sepsis, we suggest that our guiding principle to avoid plasma levels above 25 microliter/ml is reasonable. In 35 out of 78 patients an otological examination of the newborns was performed within 13 months after streptomycin treatment and no signs of hearing defects were noted.

Quantitation of phenobarbital and its main metabolites in human urine.

A method for the quantitative determination of phenobarbital and free and conjugated p-hydroxyphenobarbital in urine samples is described. The method includes initial extraction, purification on a small chromatographic column and finally determination by gas chromatography. The barbituric acids are methylated by trimethylanilinium hydroxide which serves as a "flash heater" methylating agent. The conjugate of p-hydroxyphenobarbital, which appears to be a glucuronide, is hydrolysed with hydrochloric acid.

Plasma concentrations of phenobarbital in the treatment of seizures in newborns.

The plasma concentration of phenobarbital given as anticonvulsive treatment in the newborn period has been followed in 18 infants. With constant daily doses, the drug accummulated for at least 5 days. After intramuscular injection of a single dose, 90% of the peak concentration was reached within 4 hours in 8 of the 10 infants. The peak concentration (in mug/ml) approximately equalled 1.3 x the dose (in mg/kg). Absorption after oral administration was less reliable. In 12 of the infants the clinical course allowed attempts to evaluate the anticonvulsive effect of phenobarbital. In 4 cases the convulsions continued. In those 8 infants where phenobarbital seemed to be effective, the approximate range of phenobarbital concentration when convulsions ceased was 12-30 mug/ml. Phenobarbital half-life ranged between 59 and 182 hours. In some infants the rate of phenobarbital disappearance from the plasma varied considerably from day to day. The pathological conditions causing seizures probably influence the distribution, metabolism and excretion of the drug. For the often seriously ill infants with convulsions it is therefore difficult to construct rational maintenance dose schedules, and optimal dosage must be based on repeated determinations of the plasma concentration.