Pharmacokinetics relevant to the anti-carcinogenic and anti-tumor activities of glucarate and the synergistic combination of glucarate:retinoid in the rat.

Alone and in synergistic combination with retinoids, dietary glucarate inhibits both the chemical induction and growth of rat mammary tumors. To investigate the pharmacokinetics of glucarate, [14C]glucarate was synthesized, converted to the calcium salt, and administered to rats bearing primary mammary tumors. When given by gavage, [14C]glucarate, as the calcium salt, showed a biphasic response in the blood. After peaking within 1 hr of administration at a level of 0.4 mumol/mL (normal endogenous level is approximately 0.04 mumol/mL), its plasma concentration dropped to 0.1 mumol/mL at 3 hr. In the second phase, there was a semilog increase to 0.6 mumol/mL at 15 hr, followed by a slow rise to 0.75 mumol/mL at 24 hr. Of the 38% of the administered glucarate that was recovered, 38% was excreted in the urine, and 30% remained in the gastrointestinal tract at 24 hr. Glucarate was concentrated 3- to 4-fold in the liver and intestinal mucosa, compared to the level in serum. With minor exception, the pharmacokinetics of [14C]13-cis-retinoic acid administered by gavage to rats was similar or not the semipurified diets were supplemented with 64 mmol/kg of calcium glucarate. During the interval between 5 and 10 hr post-administration of [14C]13-cis-retinoid, there was a transient 35-50% rise in the plasma level in rats on the glucarate-supplemented diet. This rise had no observable effect on the level of retinoid in major organs or in the tumor. A glucarate-binding protein was detected in the tumor cytosol. This potential receptor had a Ka of 1.49 x 10(7) M-1.