Pharmacokinetics of stable isotopically labeled L-histidine in humans and the assessment of in vivo histidine ammonia lyase activities.
The pharmacokinetics of L-histidine in humans has been investigated to evaluate the in vivo histidine ammonia lyase system for the conversion of L-histidine to urocanic acid. Two healthy volunteers (subjects A and B) received a single 100-mg oral dose of L-[3,3-2H2,1',3'-15N2]histidine. Blood and urine samples were obtained over 24 hr after the administration and analyzed by stable isotope dilution ms. Labeled L-histidine was rapidly absorbed, and a maximum plasma concentration of L-histidine was observed at 30 min (1057.6 ng/ml) in subject A and at 60 min (1635.6 ng/ml) in subject B after oral administration. Pharmacokinetic parameters were calculated based on a two-compartment model. Labeled L-histidine in subject A (t1/2 = 1.0 hr) was eliminated approximately twice faster than that in subject B (t1/2 = 1.9 hr). Total body clearances were 70.0 liters/hr in subject A and 30.0 liters/hr in subject B. The low ratios of the renal clearance to the total body clearance (1.04% for subject A and 0.43% for subject B) indicated that most of L-histidine was eliminated via the nonrenal processes. L-Histidine was rapidly metabolized to urocanic acid. Maximum plasma concentrations of urocanic acid were 59.61 ng/ml at 30 min for subject A and 46.10 ng/ml at 60 min for subject B. The slope of the plot of urinary excretion rate of urocanic acid vs. the plasma concentration of unchanged L-histidine was demonstrated to reflect the metabolic clearance of L-histidine to urocanic acid. The method of evaluating the in vivo human histidine ammonia lyase activities discussed in this study offers a significant value with regard to the biochemical and clinical elucidations of the heterogeneity of histidinemia.
Furuta
T
T
Department of Medicinal Chemistry and Clinical Pharmacy, Tokyo College of Pharmacy, Japan.
Okamiya
K
K
Shibasaki
H
H
Kasuya
Y
Y
D000328:Adult; D003903:Deuterium; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006639:Histidine / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006638:Histidine Ammonia-Lyase / Q000378:metabolism*; D006801:Humans; D008297:Male; D014560:Urocanic Acid / Q000097:blood
D006639:Histidine; D003903:Deuterium; D006638:Histidine Ammonia-Lyase; D014560:Urocanic Acid