Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester.
Tryptophan ethyl ester, a lipid-soluble tryptophan derivative, was used to bypass defective gastrointestinal neutral amino acid transport in a child with Hartnup disease. The child's baseline tryptophan concentrations in serum (20 +/- 6 microM) and cerebrospinal fluid (1.0 +/- 0.2 microM) were persistently less than 50% of normal values. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, was also less than 50% of normal (21 +/- 2 ng/ml). Serum tryptophan concentrations increased only modestly and briefly after an oral challenge with 200 mg/kg of oral L-tryptophan, reflecting the absorptive defect. An oral challenge with 200 mg/kg of tryptophan ethyl ester resulted in a prompt increase in serum tryptophan to a peak of 555 microM. Sustained treatment with 20 mg/kg q6h resulted in normalization of serum (66 +/- 15 microM) and cerebrospinal fluid tryptophan concentrations (mean = 2.3 microM). Cerebrospinal fluid 5-HIAA increased to more normal concentrations (mean = 33 ng/ml). No toxicity was observed over an 8-mo period of treatment, chronic diarrhea resolved, and body weight, which had remained unchanged for 7 mo before ester therapy, increased by approximately 26%. We concluded that tryptophan ethyl ester is effective at circumventing defective gastrointestinal neutral amino acid transport and may be useful in the treatment of Hartnup disease.
Jonas
A J
AJ
Department of Pediatrics, Harbor-UCLA Medical Center, Torrance 90502.
Butler
I J
IJ
D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002675:Child, Preschool; D005260:Female; D006250:Hartnup Disease / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D008297:Male; D009536:Niacinamide / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000134:cerebrospinal fluid; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use
D000596:Amino Acids; D009536:Niacinamide; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C025166:tryptophan ethyl ester; D014364:Tryptophan