Transplacental and mammary passage of radioactivity in rats treated vaginally and orally with [14C]propranolol.
The milk transfer, maternal-fetal distribution, and disposition of the antihypertensive/spermicidal agent propranolol were studied in pregnant and lactating rats. Single doses (10 mg/kg) of an aqueous solution of [14C]propranolol were administered either orally (po) or intravaginally (ivg) on gestational d 15, or on postpartum d 7-10. Upon ivg administration, [14C]propranolol was quickly transferred to systemic circulation and the mean blood [14C] concentrations were significantly greater during the first 0.25-2 h than in po dosed counterparts. About 98% of the ivg applied dose was absorbed after 6 h in gravid rats, and the combined 6-h excretions of radioactivity in the urine (ivg = 24.6%; po = 22.9%) and feces (ivg = 16.8%; po = 14.6%) were equivalent in both groups. At the end of 6 h, the levels of [14C] in the urinary bladder, adrenal, uterus, ovary, spleen, skeletal muscle, brain, heart, lung and fat were significantly higher in ivg treated rats than po dosed animals. Compared with the maternal plasma (ivg = 0.76; po = 0.88 microgram/ml), the mean concentrations of [14C] in the placentas were similar in both groups, while the amounts of [14C] were three to five times lower in the amniotic fluids and the fetuses of both po and ivg treated dams. In lactating rats, over 99% of the administered radioactivity was absorbed from the vagina within 6 h. The blood concentrations of [14C] were significantly elevated at 0.5 and 1 h in the per vaginam treated animals, and afterward the disappearance rate of [14C] followed a similar course in both groups. Following ivg application, the milk radioactivity peaked at 0.5 h and declined rapidly. However, the appearance of [14C] in milk was rather slow after oral dosing: the milk [14C] peaked between 2 and 3 h posttreatment and remained steady thereafter. The milk to blood (M/B) [14C] concentration ratios were markedly greater during 0.5 to 1 h in the ivg group than in their po dosed counterparts. At 6 h, the [14C] levels in the whole blood, plasma, milk, and mammary gland were virtually equivalent in the ivg and po treated females. Comparison of the areas under the milk [14C] concentration-time curves (AUCs) indicated that the milk availability of [14C] was about 31% more in dams dosed vaginally. These data suggest that route of administration alters the disposition and milk excretion of [14C]propranolol-derived radioactivity in pregnant and lactating rats.
Buttar
H S
HS
Drug Toxicology Division, Health and Welfare Canada, Ottawa.
Moffatt
J H
JH
Bura
C
C
D000042:Absorption; D000282:Administration, Intravaginal; D000284:Administration, Oral; D000653:Amniotic Fluid / Q000032:analysis; D000818:Animals; D002250:Carbon Radioisotopes; D005260:Female; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000378:metabolism*; D011247:Pregnancy; D011433:Propranolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D012588:Scintillation Counting; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D011433:Propranolol