madman
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Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review
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.
Key Points
Supplemental arginine therapy improves nitric oxide regulation in cardiovascular diseases associated with endothelial dysfunction.
Clinical pharmacology of arginine or citrulline, the two forms of exploratory clinical arginine supplement therapies, is not well understood.
Well-designed pharmacokinetic-pharmacodynamic studies are needed to establish exposure-response relationships of citrulline/arginine therapy for cardiovascular diseases.
8 Conclusions
Supplemental arginine has shown potential for therapeutic use in different diseases in both adult and pediatric age groups, and in both preclinical and clinical studies, largely because of its crucial role as an endogenous amino acid substrate in NO regulation. It is currently available in intravenous or oral dosage forms. The arginine precursor, citrulline, is available in oral forms; an intravenous preparation is being investigated in clinical trials in children undergoing cardiopulmonary bypass surgery but is not yet available. Ingestion of watermelon, a citrulline-rich fruit, has also been used in clinical studies to improve arginine levels. Citrulline appears to be more efficient than arginine in enhancing systemic arginine concentration. In several pilot clinical studies, arginine/citrulline supplementation improved conditions in some life-threatening diseases in children, including inborn errors of ureagenesis, MELAS syndrome, and PH. However, widespread clinical application is limited because the pharmacokinetics and the dose–response or exposure–response relationships of arginine/citrulline are yet to be characterized. Arginine follows complex pharmacology that depends on several confounding factors, such as baseline variations of arginine due to developmental and disease state, age, disease condition, pregnancy, etc. Pharmacokinetic studies of arginine/citrulline in diseased or special populations are not adequate to inform appropriate dosing guidance. Research directed toward understanding the PK/PD relationship of arginine, given either as arginine or citrulline supplements, in different age groups and disease conditions is critical for its translation from bench to bedside.
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.
Key Points
Supplemental arginine therapy improves nitric oxide regulation in cardiovascular diseases associated with endothelial dysfunction.
Clinical pharmacology of arginine or citrulline, the two forms of exploratory clinical arginine supplement therapies, is not well understood.
Well-designed pharmacokinetic-pharmacodynamic studies are needed to establish exposure-response relationships of citrulline/arginine therapy for cardiovascular diseases.
8 Conclusions
Supplemental arginine has shown potential for therapeutic use in different diseases in both adult and pediatric age groups, and in both preclinical and clinical studies, largely because of its crucial role as an endogenous amino acid substrate in NO regulation. It is currently available in intravenous or oral dosage forms. The arginine precursor, citrulline, is available in oral forms; an intravenous preparation is being investigated in clinical trials in children undergoing cardiopulmonary bypass surgery but is not yet available. Ingestion of watermelon, a citrulline-rich fruit, has also been used in clinical studies to improve arginine levels. Citrulline appears to be more efficient than arginine in enhancing systemic arginine concentration. In several pilot clinical studies, arginine/citrulline supplementation improved conditions in some life-threatening diseases in children, including inborn errors of ureagenesis, MELAS syndrome, and PH. However, widespread clinical application is limited because the pharmacokinetics and the dose–response or exposure–response relationships of arginine/citrulline are yet to be characterized. Arginine follows complex pharmacology that depends on several confounding factors, such as baseline variations of arginine due to developmental and disease state, age, disease condition, pregnancy, etc. Pharmacokinetic studies of arginine/citrulline in diseased or special populations are not adequate to inform appropriate dosing guidance. Research directed toward understanding the PK/PD relationship of arginine, given either as arginine or citrulline supplements, in different age groups and disease conditions is critical for its translation from bench to bedside.
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