Pharmacokinetic Studies of L-DOPS (L-threo-3,4-Dihydroxyphenylserine) in Renal Failure Rats

The pharmacokinetics of (-)-(2S, 3R) -2-amino-3-hydroxy) -3 (3, 4-dihydoxy-phenyl)propiconic acid (L-DOPS), the precursor of (-)-norepinephrine (NE), were studied, using 14C-L-DOPS labelled at C-3 position (10 mg/kg), in rats with renal failure. After single oral administration of 14C-L-DOPS (10 mg/kg) to 5/6 partially nephrectomized rats, the serum 14C halflife (T1/2) was longer and the maximum concentration (Cmax), the area under the curve (AUC0-48) were 3, 10 times higher than those of the sham-operated rats respectively. Nevertheless, the excretion of radioactivity into urine or feces within 72 hr after administration were not significantly different between nephrectomized and sham-operated normal rats. L-DOPS, (-)-(2S, 3R)-2-amino-3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-propionic acid (3-OM-DOPS), 3, 4-dihydroxybenzoic acid (Protocatechuicacid, PA), 4-hydroxy-3-methoxybenzoic acid (Vanillic acid, VA), their conjugates and 3, 4-dihydroxytoluene conjugate were identified as the metabolites present in the serum at 24 hr after single oral administration of 14C-L-DOPS (10 mg/kg) to completely nephrectomized rats. VA and PA conjugates were measured as the major metabolites. 14C levels in major tissues were changed in parallel with 14C serum levels and no particular 14C increase in tissue was found in 5/6 partially nephrectomized rats. The radioactivity decreased in tissues rapidly and no tissue with specific 14C accumulation was observed. During the consecutive oral administration of 14C-L-DOPS (10 mg/kg/day) to 5/6 partially nephrectomized rats for 7 days, the 14C serum levels profile on the 4th day and 7th day were similar to those observed on the 1st day. After repeated oral administration of 14C-L-DOPS (10 mg/kg) for 7 days, the elimination rate of 14C in tissues was slower than that observed on the 1st day, however 14C decreased below 1.0 μg eg./g. in all tissues at 72 hr and no particular accumulation in any tissue was found.