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Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review

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Abstract

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, l-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. l-citrulline, a natural precursor of l-arginine, is more bioavailable than l-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure–response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    Jahidur Rashid, Shaun S. Kumar, Kathleen M. Job & Xiaoxi Liu

  2. Division of Neonatology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    Candice D. Fike

  3. Department of Pediatrics, Wright State University, Boonshoft School of Medicine, Dayton Children’s Hospital, One Children’s Plaza, Dayton, OH, 45404-1815, USA

    Catherine M. T. Sherwin

  4. Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA

    Catherine M. T. Sherwin

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  1. Jahidur Rashid
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  2. Shaun S. Kumar
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  3. Kathleen M. Job
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  4. Xiaoxi Liu
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  5. Candice D. Fike
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  6. Catherine M. T. Sherwin
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Correspondence to Catherine M. T. Sherwin.

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JR, SSK, KMJ, XL, CDF, and CMS have no conflicts of interest that are directly relevant to the content of this review.

Funding

This article was funded by NIH/NHLBI (Grant no. R34HL142995).

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Rashid, J., Kumar, S.S., Job, K.M. et al. Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review. Pediatr Drugs 22, 279–293 (2020). https://doi.org/10.1007/s40272-020-00384-5

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