Comparative distribution and metabolism of triamcinolone acetonide and cortisol in the rat embryomaternal unit

Abstract

Triamcinolone acetonide (TAC) is teratogenic in rats while cortisol has been reported as not teratogenic. The objective of this investigation was to determine whether this difference in teratogenicity could be due to a difference in the metabolism and distribution of the parent compound in the embryomaternal unit. 3H-TAC and 14C-cortisol were administered intramuscularly to pregnant rats on day 12 of gestation. These dams were killed at each of the following time points after injection: 0.5, 1, 3, 6 and 24 hr. Maternal plasma and embryos were analyzed by high performance liquid chromatography (HPLC) and liquid scintillation counting. The plasma concentration of parent TAC was significantly greater than that for parent cortisol at all time points. The plasma elimination half-life for TAC, 86 min, was also calculated to be significantly longer than that for cortisol, 8 min. Furthermore, the percentage of total plasma radioactivity representing HPLC resolved TAC was much higher than that representing cortisol at all time points. The concentration of TAC in the embryos was significantly greater than for cortisol at all time points. The elimination half-life for unchanged TAC in the embryos was 142 min compared to 22 min for cortisol. The percentage of total radioactivity in the embryos representing unchanged TAC was similar to that found in maternal plasma while the percentage of total radioactivity representing unchanged cortisol was much lower than that found in maternal plasma. These findings support the hypothesis that differences in the distribution and metabolism of the parent compound are a critical factor in determining the teratogenicity of that compound.

Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes

“…In addition, further studies are required to rule out chance findings. Nevertheless, intramuscular triamcinolone was shown to be teratogenic in animals and has been shown to affect lung development, [11][12][13] which is consistent with our findings. Although adjustment was made on maternal AR (indication) and other known risk factors for major congenital malformations (maternal asthma and severity of maternal respiratory diseases), residual confounding cannot be excluded completely.…”

“…Although we could not adjust for these variables, the fact that our findings are consistent with those of Kallen et al, 9 who adjusted for these variables, suggests that the level of confounding would not have changed our conclusions. In addition, defects identified in our study have been seen in animal studies, [11][12][13] suggesting a probable mechanism of action. Although confounding by indication was reduced by the fact that exposure to other intranasal corticosteroids was not associated with the outcomes studied, confounding can still occur because of different patterns of prescribing, and hence residual confounding cannot be completely ruled out.…”

“…Recently, the FDA approved intranasal triamcinolone OTC sales with pregnancy category C, which could partly be explained by the fact that intramuscular triamcinolone acetonide was found to be teratogenic in animals. 11,12 Indeed, triamcinolone acetonide has the potential to have a potent teratogenic effect on various mammalian fetal tissues, as well as a steroid effect on the lung, fetal growth retardation, and cleft palate anomalies. 13 At present, no human pregnancy data are available for intranasal triamcinolone.…”

Maternal Smoking Increases Xenobiotic Metabolism in Placenta but Not Umbilical Vein Endothelium

“…Such low PAH concentrations would then be insufficient to induce AHH activity in umbilical vein endothelium, consistent with the data in Figure 3. In support of this concept, Rowland et al (28) have recently presented data suggesting that placental clearance of cortisol contributes to reduced levels of this potential teratogen in rat fetuses. This finding may explain why the rat is relatively resistant to the teratogenic actions of maternally administered cortisol.…”

Palatal Slit and Cleft Palate in Rats Treated with Glucocorticoids II. Comparative Teratogenicity of Prednisolone, Triamcinolone Acetonide and Hydrocortisone

“…It is important to define the difference in potential on a quantitative basis and determine the extent of interspecies variation in the relative potentials of various glucocorticoids. Relative potentials of various glucocorticoids to induce cleft palate in rats have been well studied (Walker, 1971;Hendrickx, 1983a, 1983b;Rowland et al, 1983). Thus, in the present study, we studied induction of another palatal defect, palatal slit, by a few other glucocorticoids, prednisolone, triamcinolone acetonide and hydrocortisone in rat fetuses.…”