Roger A. Yeary

Acute toxicity of drugs in newborn animals

The acute toxicities of 30 compounds were compared in 1- to 3-day-old and adult(150 gram) rats. The effect of maturation on acute toxicity was generally consistent within a pharmacologic class of compounds. Only 16 of the 30 compounds were particularly more toxic to the newborn rat. The central nervous system depressants were more toxic in the immature rat whereas the central nervous system stimulants were less toxic in the newborn as compared with adult rats.

Activated Charcoal Decreases Plasma Bilirubin Levels in the Hyperbilirubinemic Rat

Summary: The effectiveness of phototherapy and activated charcoal feeding for reducing plasma bilirubin concentrations was studied in the hyperbilirubinemic Gunn rat. The feeding of charcoal alone was just as effective in reducing plasma bilirubin concentrations as continuous phototherapy. An additive effect on reducing plasma bilirubin concentration was observed when phototherapy and the feeding of charcoal were administered together. The feeding of a 5% charcoal diet to weanling Gunn rats for 8 wk had no effect on growth rate.

Effect of Sulfadimethoxine on Tissue Distribution of [14C]Bilirubin in the Newborn and Adult Hyperbilirubinemic Gunn Rat

Extract: Sulfadimethoxine significantly reduced plasma bilirubin levels and altered the tissue bilirubin distribution in both the newborn and the adult Gunn rat. The majority of the unbound bilirubin appeared to distribute preferentially to the intestine and liver in the newborn, whereas in the adult the unbound bilirubin was taken up primarily by the liver. The bilirubin content of brain tissue from both age groups was significantly higher after sulfadimethoxine treatment.Speculation: A decrease in the available extravascular bilirubin binding sites, indicated by an increased concentration of bilirubin in the carcass and an apparent decreased capacity of the liver of the newborn Gunn rat to bind bilirubin, would suggest that kernicterus in the Gunn rat neonate is associated with increased bilirubin concentrations in the brain. However, the similar uptake of bilirubin by the brain tissue of both the newborn and the adult Gun rat raises the question of increased sensitivity of the newborn brain to bilirubin toxicity.

Protein binding of bilirubin: Comparison of in vitro and in vivo measurements of bilirubin displacement by drugs

Abstract A comparison of methods for the in vitro and in vivo measurement of unbound bilirubin in the presence of plasma proteins, drugs and other chemicals was made to determine the best methods for preclinical investigation of new drugs that may be used during the perinatal period. The methods examined included: equilibrium dialysis, binding of 2-(4′-hydroxybenzeneazo)benzoic acid to serum, spectral shift of free and albumin-bound bilirubin, displacement of bilirubin from albumin to mitochondria in vitro, drug-mediated decrease in plasma bilirubin in hyperbilirubinemic Gunn rats, and Sephadex gel filtration for separation of protein bound and unbound bilirubin. Sephadex gel filtration appeared to be the most useful method for measurement of unbound bilirubin. There was good agreement between in vitro studies of sulfadimethoxine and salicylate displacement of bilirubin using Sephadex gel filtration and in vivo studies in the Gunn rat. Studies of bilirubin displacement in the icteric Gunn rat provide a basis for establishing realistic conditions of drug dosage, the time course of drug action and the possible role of metabolites where there is insufficient information to establish the appropriate conditions for in vitro investigations.

Bilirubin Binding to Hepatic Y and Z Protein (LIGANDIN): Tissue Bilirubin Concentrations in Phenobarbital Treated Gunn Rats

Summary NaP treatment significantly reduced plasma bilirubin levels in the (jj) Gunn rat. It is suggested that NaP significantly increased extravascular bilirubin binding in the liver by induction of the synthesis of Y anion binding protein. The changes in bilirubin concentration of blood and other tissues subsequent to NaP treatment were consistent with the establishment of a new tissue bilirubin equilibrium. The authors are grateful to Kathy Wise and Richard Brant for their technical assistance.

Activated charcoal as an adjunct to phototherapy for neonatal jaundice.

The effectiveness of activated charcoal as an adjunct to phototherapy in reducing plasma bilirubin levels was studied in the jaundiced rat. The administration of charcoal either by feeding or gavage was effective in reducing plasma bilirubin levels in both the adult and suckling jaundiced rat. The combination of charcoal feeding and phototherapy in the adult rat was additive in that the bilirubin levels were significantly lower when compared to levels of the rats given charcoal alone. Plasma bilirubin levels were significantly reduced in the suckling jaundiced rat given either charcoal or charcoal together with phototherapy, however, the combination of treatments did not appear to be additive. These data suggest that charcoal could be a useful adjunct to phototherapy by binding bilirubin in the intestinal lumen and reducing the potential for the enterohepatic circulation of unconjugated bilirubin. Charcoal combined with phototherapy may also reduce the intensity of phototherapy needed to effectively lower plasma bilirubin levels.

Decreased conjugation of p-aminobenzoic acid in the icteric newborn Gunn rat☆

Abstract The metabolism of p -aminobenzoic acid in the icteric and non-icteric Gunn rat was studied. The urinary metabolites of p -aminobenzoic acid identified were the parent compound, p -aminohippuric acid and p -aminobenzoic acid glucuronide. The urinary data indicated that the icteric Gunn rat not only excreted significantly less of the p -aminobenzoic acid within 24 hr but also excreted significantly less of the compound as the glucuronide. In the newborn icteric rat, the major excretory product was the unchanged p -aminobenzoic acid, whereas in the adult most of the drug was excreted as the glycine conjugate. The data in vivo and in vitro indicated that the icteric newborn rat converts significantly less p -aminobenzoic acid to p -aminohippuric acid than does the non-icteric rat. The synthesis of p -aminohippuric acid is quite low in both genotypes at birth, but rapidly approaches adult levels at 30 days of age. In view of the data presented, the increased toxicity of p -aminobenzoic acid in the 2-day-old icteric Gunn rat may be the result of a decreased p -aminobenzoic add metabolism in these rats due to a deficiency in the activity of the enzyme UDP-glucuronyltransferase and possibly glycine- N -acyltransferase.

Developmental changes in p-nitrophenol glucuronidation in the gunn rat☆

Abstract Non-icteric heterozygous Gunn rats conjugated p-nitrophenol more readily than icteric homozygous rats at 2, 14 and 28 days of age. Heterozygous females, 65–70 days old, also formed the glucuronide more readily than homozygous recessives of the same age, but the results for males were not statistically significant. Both genotypes had comparatively low levels of enzyme activity at birth, with absolute levels and rate of maturation lowest in the icteric homozygous recessives.

Comparative toxicity studies on glucuronide-forming compounds in icteric and nonicteric newborn Gunn rats

Comparative studies on the toxicity of glucuronide-forming compounds were conducted in icteric and nonicteric newborn Gunn rats. Toxicity was quantitated by determining the L.D. 50 in two-day-old rats. Statistically significant differences in toxicity between icteric and nonicteric littermates were found in six of ten glucuronide-forming compounds. This animal model appears to be a useful addition to preclinical toxicologic investigations with new drugs that may be given to premature and newborn infants.

Activation of hepatic microsomal glucuronyltransferase from gunn rats by exposure to light

Abstract Exposure of hepatic microsomes from icteric and nonicteric rats to 250 foot candles of blue fluorescent light for 4 hours at 4–6°C significantly increased the activity of UDPglucuronyltransferase activity using p-nitrophenol as a substrate. The light exposure reduced serum bilirubin concentration from icteric rats or bilirubin of fortified human serum albumin by 70 per cent but there was no difference in light activation of hepatic microsomes from icteric or nonicteric rats. Light exposure also decreased the activation of UDPglucuronyltransferase produced by Triton X-100.