TY - JOUR
T1 - Waste nitrogen excretion via amino acid acylation
T2 - Benzoate and phenylacetate in lysinuric protein intolerance
AU - Simell, Olli
AU - Sipila, Ilkkä
AU - Rajantie, Jukka
AU - Valle, David L.
AU - Brusilow, Saul W.
PY - 1986/11
Y1 - 1986/11
N2 - Benzoate and phenylacetate improve prognosis in inherited urea cycle enzyme deficiencies by increasing waste nitrogen excretion as amino acid acylation products. We studied metabolic changes caused by these substances and their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric protein intolerance (LPI), under strictly standardized induction of hyperammonemia. Five patients with LPI received an intravenous infusion of 6.6 mmol/kg l-alanine alone and separately with 2.0 mmol/kg of benzoate or phenylacetate in 90 min. Blood for ammonia, serum urea and creatinine, plasma benzoate, hippurate, phenylacetate, phenylacetylgluta-mine, and amino acids was obtained at 0, 120, 180, and 270 min. Urine was collected in four consecutive 6-h periods. Alanine caused hyperammonemia: maximum increase 107, 28-411 μM (geometric mean, 95% confidence interval); ammonia increments were nearly identical after alanine + benzoate (60, 17-213 μM)and alanine + phenylacetate (79, 13-467 μM) (NS). Mean plasma benzoate was 6.0 mM when extrapolated to the end of alanine + benzoate infusions; phenylacetate was 4.9 mM at the end of alanine + phenylacetate. Transient toxicity (dizziness, nausea, vomiting) occurred in four patients at the end of combined infusions, and we suggest upper therapeutic plasma concentrations of 4.5 mM for benzoate and 3.5 mM for phenylacetate. Benzoate and phenylacetate then decreased following first-order kinetics with ti/2s of 273 and 254 min, respectively. Maximal plasma hippurate (0.24, 0.14-0.40 mM) was lower than maximal phenylac-etylglutamine (0.48, 0.22-1.06 μM, p = 0.008). Orotic acid excretion was 5.62, 1.84-17.14 μmol/kg per h after alanine, but only 1.07, 0.04-25.62 jtmol/kg per h after alanine + benzoate (p <0.151) and 2.74,0.01-16.25 jimol/ kg per h after alanine + phenylacetate(p < 0.016). Urea excretions were in the same range after all loads. Urinary hippurate nitrogen after alanine + benzoate and phenyl-acetylglutamine nitrogen after alanine + phenylacetate accounted for an average of 12 and 22 of that in urea in the first 6 h. Of the benzoate and phenylacetate given, 65 and 51% were excreted in 24 h as hippurate and phenylacetylglutamine, respectively; less than 3.5% appeared unchanged in urine.
AB - Benzoate and phenylacetate improve prognosis in inherited urea cycle enzyme deficiencies by increasing waste nitrogen excretion as amino acid acylation products. We studied metabolic changes caused by these substances and their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric protein intolerance (LPI), under strictly standardized induction of hyperammonemia. Five patients with LPI received an intravenous infusion of 6.6 mmol/kg l-alanine alone and separately with 2.0 mmol/kg of benzoate or phenylacetate in 90 min. Blood for ammonia, serum urea and creatinine, plasma benzoate, hippurate, phenylacetate, phenylacetylgluta-mine, and amino acids was obtained at 0, 120, 180, and 270 min. Urine was collected in four consecutive 6-h periods. Alanine caused hyperammonemia: maximum increase 107, 28-411 μM (geometric mean, 95% confidence interval); ammonia increments were nearly identical after alanine + benzoate (60, 17-213 μM)and alanine + phenylacetate (79, 13-467 μM) (NS). Mean plasma benzoate was 6.0 mM when extrapolated to the end of alanine + benzoate infusions; phenylacetate was 4.9 mM at the end of alanine + phenylacetate. Transient toxicity (dizziness, nausea, vomiting) occurred in four patients at the end of combined infusions, and we suggest upper therapeutic plasma concentrations of 4.5 mM for benzoate and 3.5 mM for phenylacetate. Benzoate and phenylacetate then decreased following first-order kinetics with ti/2s of 273 and 254 min, respectively. Maximal plasma hippurate (0.24, 0.14-0.40 mM) was lower than maximal phenylac-etylglutamine (0.48, 0.22-1.06 μM, p = 0.008). Orotic acid excretion was 5.62, 1.84-17.14 μmol/kg per h after alanine, but only 1.07, 0.04-25.62 jtmol/kg per h after alanine + benzoate (p <0.151) and 2.74,0.01-16.25 jimol/ kg per h after alanine + phenylacetate(p < 0.016). Urea excretions were in the same range after all loads. Urinary hippurate nitrogen after alanine + benzoate and phenyl-acetylglutamine nitrogen after alanine + phenylacetate accounted for an average of 12 and 22 of that in urea in the first 6 h. Of the benzoate and phenylacetate given, 65 and 51% were excreted in 24 h as hippurate and phenylacetylglutamine, respectively; less than 3.5% appeared unchanged in urine.
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U2 - 10.1203/00006450-198611000-00011
DO - 10.1203/00006450-198611000-00011
M3 - Article
C2 - 3099249
AN - SCOPUS:0022544133
SN - 0031-3998
VL - 20
SP - 1117
EP - 1121
JO - Pediatric research
JF - Pediatric research
IS - 11
ER -