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Title: A randomized trial to study the comparative efficacy of phenylbutyrate and benzoate on nitrogen excretion and ureagenesis in healthy volunteers

Author
item NAGAMANI, SANDESH - BAYLOR COLLEGE OF MEDICINE
item AGARWAL, UMANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item TAM, ALLISON - BAYLOR COLLEGE OF MEDICINE
item AZAMIAN, MAHSHID - BAYLOR COLLEGE OF MEDICINE
item MCMEANS, ANN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item DIDELIJA, INKA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item MOHAMMAD, MAHMOUD - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item MARINI, JUAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: Genetics in Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/16/2017
Publication Date: 10/12/2017
Citation: Nagamani, S.C., Agarwal, U., Tam, A., Azamian, M., McMeans, A., Didelija, I.C., Mohammad, M.A., Marini, J.C. 2017. A randomized trial to study the comparative efficacy of phenylbutyrate and benzoate on nitrogen excretion and ureagenesis in healthy volunteers. Genetics in Medicine. https://dx.doi.org/10.1038/gim.2017.167.
DOI: https://doi.org/10.1038/gim.2017.167

Interpretive Summary: Urea cycle disorders result in a deficiency in the detoxification of nitrogen generated by protein metabolism and in the production of urea. Children with these disorders are fed low protein diets and as a consequence their growth is compromised. Certain pharmaceuticals (phenylbutyrate and benzoate) are used to bind nitrogen containing compounds and excreting them in the urine which allow for feeding these patients adequate protein diets. There are no studies comparing phenylbutyrate and benzoate, despite the large differences in the cost of these therapies. Here we showed that phenylbutyrate was more effective at excreting nitrogen than benzoate. However, benzoate resulted in a reduced cost per unit of nitrogen excreted. The combination of both resulted in a cost effective therapy maximizing nitrogen excretion and reducing costs.

Technical Abstract: Alternative pathway therapy with benzoate and phenylbutyrate is widely used in the treatment of urea cycle disorders, but detailed pharmacokinetic studies and comparative efficacy on nitrogen excretion are lacking. We conducted a randomized, three arm, cross over trial in healthy volunteers to study pharmacokinetics and comparative efficacy of phenylbutyrate (7.15 g/m-2 BSA per day), benzoate (5.5 g/m-2 BSA per day)1 and a combination of the two medications (MIX arm; 3.575 g phenylbutyrate and 2.75 g benzoate/m-2 BSA per day) on nitrogen excretion. Stable isotopes were used to study effects on urea production and dietary nitrogen disposal. The conjugation efficacy for both phenylbutyrate and benzoate was 65%; phenylbutyrate the conjugation efficacy phenylbutyrate was greater with the lower dose administered in the MIX arm. Phenylbutyrate and MIX treatments were more effective in excreting nitrogen than benzoate. Nitrogen excretion as a drug conjugate was similar between phenylbutyrate and MIX arms. Nitrogen excreted per USD was higher with combination therapy compared to phenylbutyrate. Phenylbutyrate was more efficacious than benzoate at disposing nitrogen. Combinatorial therapy with phenylbutyrate and benzoate has the potential to significantly reduce the cost of treatment cost without compromising the amount of nitrogen conjugated.