Diaplacental Transfer of Thiampheni Col (TAP) in Pregnant Rats during Late Organogenesis

Abstract

The application of chemotherapeutic agents during organogenesis which in mammals specifically interfere with mitochondrial biogenesis and function leads to impaired embryonal development. Whereas lower doses of chloramphenicol (CAP) or TAP lead to reversible inhibition of both mitochondrial and embryonal development, higher doses lead to embryolethality via mitochondrial impairment (D. Oerter & R. Bass, Naunyn-Schmiedeberg’s Arch. Pharmacol. 290, 175, 1975; R. Bass & D. Oerter, ibid. 296, 191, 1977). The effects were also dependent on time and duration of treatment. CAP in the rat is very rapidly eliminated as glucuronide with a serum half-life of about 25 min (J. Alvin & B.N. Dixit, Biochem. Pharmacol. 23, 139, 1974). 1 g/kg CAP infused i.v. for 24 h (day 12 of gestation) yields levels in maternal serum and fetal tissues of about 20 μg per ml or g, and reversibly inhibits mitochondrial protein synthesis and embryonal development. 125 mg TAP/kg (day 10 and 11), or 80 mg/kg (days 10–13) strongly inhibit mitochondrial biosynthesis and lead to embryolethality. As a first prerequisite to extrapolate the experimental findings to the human situation the pharmacokinetic behaviour of TAP in rats was studied after a single s.c. injection on day 12.