Propionyl-L-Carnitine
1. Identity: Chemical Names, Natural Source, and Common Forms
Propionyl-L-carnitine (PLC) is a natural short-chain derivative of L-carnitine (LC), a natural amino acid that plays an important role in fatty acid metabolism. Chemically, it is a short-chain fatty ester of carnitine (3-hydroxy-4-N-trimethyl-aminobutyric acid) and is a naturally occurring substance required in mammalian energy metabolism.
Propionyl-L-carnitine (PLC), a natural odd-carbon-number, endogenous ester of L-carnitine, is found to be present in humans and animals as a minor component compared to L-carnitine (LC) and acetyl-L-carnitine (ALC). PLC, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species.
Chemical Identifiers and Synonyms
- Common synonyms include: CAR 3:0, C3:0 Carnitine, L-Carnitine propionyl ester, Levocarnitine propionate, L-Propionylcarnitine, and ST 261. The molecular formula is C10H20NO4.
- An alternate systematic name is (2R)-3-carboxy-N,N,N-trimethyl-2-(1-oxopropoxy)-1-propanaminium inner salt; it is also known as L-Carnitine propionyl ester, C3-Carnitine, and Propanoyl-L-carnitine.
- The CAS number most commonly referenced for the hydrochloride salt form is 119793-66-7 (propionyl-L-carnitine chloride), while 20064-19-1 refers to the inner salt (zwitterion) form.
Biosynthesis and Natural Source
Propionyl-L-carnitine is a naturally occurring carnitine derivative formed by carnitine acetyltransferase during beta-oxidation of uneven chain fatty acids. PLC is produced in the body and concentrated by 90% in the skeletal muscle and myocardium via an enzyme-mediated reaction involving propionyl-CoA and LC. The body can convert L-carnitine to other chemicals called acetyl-L-carnitine and propionyl-L-carnitine.
In non-vegetarians, most carnitine sources (~75%) are obtained from diet, whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine.
Common Forms and Preparations
PLC is commercially available and investigated in the following forms:
- Propionyl-L-carnitine hydrochloride (HCl): The hydrochloride salt form is used for intravenous administration in pharmacokinetic investigations; a placebo-controlled, double-blind, parallel group, dose-escalating study assessed this form in healthy males.
- Oral tablets and capsules: In clinical trials, participants received either 1 gram to 2 grams oral PLC daily.
- Glycine propionyl-L-carnitine (GPLC): As a manufactured agent, PLC is most often delivered as glycine propionyl-L-carnitine (GPLC).
- Intravenous infusion: In pharmacokinetic studies, doses of 1 g, 2 g, 4 g, and 8 g were administered as a constant-rate infusion over 2 hours.
2. Traditional and Historical Use
Propionyl-L-carnitine is not a botanical or plant-derived compound with a pre-modern traditional use. As an endogenous metabolite found in the carnitine pool of mammals, PLC was not identified and characterized as a distinct chemical entity until the mid-to-late twentieth century. PLC is currently under investigation for the treatment of peripheral artery disease. L-carnitine itself, the parent molecule, has a historical research and clinical trajectory beginning in the 1950s and 1960s as its role in fatty acid transport was elucidated, but PLC as a separate therapeutic entity emerged from pharmaceutical research in Italy in the 1980s and early 1990s, initially investigated as a metabolic cardioprotective agent.
The compound has no documented history of use in traditional herbal medicine, Ayurveda, Traditional Chinese Medicine, or other pre-modern medical systems, as it was unknown as a distinct entity prior to modern analytical biochemistry. All clinical use of PLC derives from modern pharmaceutical and nutritional supplement research, predominantly conducted in Europe (particularly Italy) beginning in the late 1980s.
3. Key Constituents, Biochemistry, and Mechanisms of Action
Structure and Biochemical Role
PLC acts as a carrier of long-chain acyl groups from activated fatty acids across the inner mitochondrial membrane into the mitochondrial matrix where they undergo Ξ²-oxidation to acetyl-CoA to obtain usable energy via the citric acid cycle. L-carnitine is an endogenous substance that acts as a carrier for fatty acids across the inner mitochondrial membrane necessary for subsequent Ξ²-oxidation and ATP production.
Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscle L-carnitine transferase. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. This anaplerotic function β replenishing Krebs cycle intermediates β is considered a key distinguishing feature of PLC relative to L-carnitine itself.
Antioxidant Activity
PLC has been documented to be an antioxidant agent, protecting tissues from oxidative damage. In particular, PLC has been documented to be capable of reducing membrane lipid peroxidation and the effects of hypoxia in cardiomyocytes, endothelial dysfunction in ischemic rabbit limbs, and in human inflammatory bowel diseases.
Endothelial and Nitric Oxide Signaling
Because of the importance of endothelial nitric oxide synthase (eNOS) and its product, the antiatherogenic molecule nitric oxide (NO), in vascular endothelial function, research has shown that PLC stimulates eNOS and its upstream activators Akt and phosphatidylinositol 3-kinase (PI3 kinase) in cultured human aortic endothelial cells (HAEC). PLC caused eNOS phosphorylation at Ser-1177, and dominant negative Akt and a novel Akt-selective inhibitor MK-2206 inhibited both PLC-mediated phosphorylation and activation of the enzyme. PI3 kinase inhibition also blocked the phosphorylation and activation of eNOS by PLC.
PLC reduces the production of reactive oxygen species (ROS) and decreases the expression of NADPH oxidase 2 (NOX2), NOX4, and ICAM-1 in human umbilical vein endothelial cells (HUVECs). Although the mechanism of action of PLC remains incompletely understood, it appears that its cardiovascular effects are in part related to vasodilatation and enhanced blood flow.
Mitochondrial Protection in Ischemia
Propionyl-L-carnitine reduces mitochondrial dysfunction induced by ischemia, preventing mitochondrial calcium overload and depletion of ATP tissue stores in a rabbit model of ischemia. One postulated mechanism is that propionyl-L-carnitine reverses the alterations in energy metabolism that occur secondary to the carnitine deficiency seen in hypertrophied myocardium.
Wound Healing and Angiogenesis
A daily oral PLC treatment improved skin flap viability and was associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation of iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and reduction of NADPH-oxidase 4 (Nox4) expression in animal studies.
4. Pharmacokinetics
PLC is an endogenous compound forming part of the carnitine pool in humans. It is currently under investigation for treatment of peripheral artery disease, and pharmacokinetic studies have assessed intravenous propionyl-L-carnitine hydrochloride.
Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC, and ALC, due to saturation of the renal tubular reabsorption process. This saturable reabsorption at the renal tubule β observed as dose-escalating exposures increase urinary excretion markedly β is a key pharmacokinetic feature shared with L-carnitine.
5. Scientific Evidence by Area of Use
5a. Peripheral Arterial Disease and Intermittent Claudication
This is the most extensively studied clinical application of PLC, with the largest body of randomized, controlled evidence.
Cochrane Systematic Review (2021): A search for relevant articles on propionyl-L-carnitine for treatment of intermittent claudication identified 12 relevant trials that matched inclusion criteria (current until July 2021). In 11 studies, participants received either 1 gram to 2 grams oral PLC (9 studies) or intravenous propionyl-L-carnitine (3 studies) per day or placebo. One study compared propionyl-L-carnitine with L-carnitine.
Meta-Analysis (NCBI/DARE): Propionyl-L-carnitine may improve exercise performance in patients with peripheral artery disease, but results from clinical trials have been inconsistent. The safety and efficacy of PLC for treatment of claudication was evaluated by a systematic review and meta-analysis of clinical trials, and 85 studies were identified, of which 13 were randomized controlled trials. Owing to database availability for the six phase III studies carried out with PLC (1 g orally, twice daily), a patient-level meta-analysis was conducted as the primary analysis. PLC (n = 440) was associated with a net 16-meter improvement (95% CI, 8β20 meters) in peak walking distance as compared with placebo (n = 427) in the primary analysis (p = 0.002).
Phase III Multi-Centre Studies: Oral propionyl-L-carnitine 1 to 3 g/day significantly improved mean maximum walking distance compared with placebo in patients with peripheral arterial obstructive disease (Fontaine Leriche stage II) in double-blind multi-centre phase III studies, with mean improvements ranging from 21 to 50% with placebo and from 33 to 73% with propionyl-L-carnitine.
Double-Blind Trial (Dal Lago et al., 1999): The study was performed on 22 patients according to a double-blind, randomized design in parallel with placebo. The drug was administered at a dosage of 1 g three times a day orally for 90 days. The authors evaluated the efficacy of propionyl-L-carnitine, a drug able to reduce peripheral resistance and protect the cells against oxidative stress damage, in patients affected by peripheral arterial obliterative disease at class II of Fontaine. In the group treated with propionyl-L-carnitine, a statistically significant increase of claudication distance, blood flow velocity, PAI-1 activity, and red blood cell deformity was observed.
Haemodialysis Patients with PAD (RCT): The trial was a randomised, double-blind, placebo-controlled trial. Sixty-four patients on haemodialysis (32 per treatment arm) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl-L-carnitine. In patients treated with propionyl-L-carnitine, significant progressive decreases were seen in plasma MDA, 4-HNE, and the NOβ/NOβ ratio from baseline. In the placebo-treated group, only weakly significant or no differences were seen. Intravenous administration of propionyl-L-carnitine to haemodialysis patients with PAD improved both haemodynamic flow and the oxidative profile.
Exercise Training Combination (Hiatt et al., 2011): In all subjects, the increase in peak walking time from baseline to month 6 was correlated with the amount of exercise training. However, although favoring PLC, the combination of exercise training and PLC did not result in a statistically significant benefit in peak treadmill performance or quality of life compared with exercise training plus placebo. This indicates that, when added to supervised exercise, PLC's incremental benefit is modest and may not reach statistical significance.
Evidence strength: Moderate. The Cochrane review and patient-level meta-analysis confirm a statistically significant but clinically modest improvement in walking distance. Results across individual trials have been inconsistent, and the evidence is insufficient to establish superiority over other vasoactive drugs, as head-to-head comparisons are lacking.
5b. Congestive Heart Failure (CHF)
Phase II Double-Blind Trial (Pucciarelli et al., 1992): A double-blind phase II study of propionyl-L-carnitine versus placebo was carried out on a group of 60 patients with mild to moderate (NYHA class II and III) congestive heart failure. The group was made up of men and women aged between 48 and 73 years in chronic treatment with digitalis and diuretics for at least 3 months and who still displayed symptoms. Thirty of these patients were chosen randomly and for 180 days, 500 mg of propionyl-L-carnitine was orally administered 3 times a day in addition to their usual treatment. After one month of treatment, the patients treated with propionyl-L-carnitine showed significant increases in maximum exercise time and ventricular ejection fraction, increases which became even more evident after 90 and 180 days. At the stated times the increases in maximum exercise time were 16.4%, 22.9%, and 25.9%, respectively. The ventricular ejection fraction increased by 8.4%, 11.6%, and 13.6%, respectively.
Multicenter Phase III Trial: The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
Phase III Multicenter Study (European Heart Journal, 1999): The objective was to evaluate the effect of propionyl-L-carnitine on exercise capacity in mild-to-moderate chronic heart failure patients treated with ACE inhibitors and diuretics. In patients with chronic heart failure, fatigue is independent of haemodynamic and neuroendocrine changes and possibly may be due to impaired muscle metabolism. Propionyl-L-carnitine, a carnitine derivative, was shown in previous studies to improve muscle metabolism. This was a phase III, double-blind, randomized, parallel, multicentre study, with evaluation of the effect of propionyl-L-carnitine vs placebo on maximum exercise duration using a bicycle exercise test.
Evidence strength: Moderate for improvement in exercise capacity markers. The predominant proposed mechanism is metabolic β improving skeletal and cardiac muscle energetics rather than directly altering cardiac structure. The large multicenter trial did not demonstrate improvement in cardiac function per se, only in exercise capacity, limiting the clinical interpretation of these findings.
5c. Stable Effort Angina
Double-Blind Crossover Trial (Cherchi et al., 1991): The effects of propionyl-L-carnitine on exercise tolerance of 12 patients with stable exertional angina were assessed in a double-blind, placebo-controlled, crossover protocol using serial exercise tests. Compared to placebo, propionyl-L-carnitine significantly increased total work from 514 Β± 199 to 600 Β± 209 W (P < 0.05) (17%) and prolonged exercise time and time to ischemic threshold. ST segment depression at the highest common work level was significantly reduced from 0.19 Β± 0.08 to 0.15 Β± 0.08 mV (P < 0.05) (21%). No significant changes were observed in heart rate, systolic blood pressure, or rate-pressure product. No side effects were observed under propionyl-L-carnitine treatment. This study shows that propionyl-L-carnitine can significantly improve exercise tolerance in patients with stable angina, most likely exerting its protective action via the metabolic pathway.
Evidence strength: Preliminary. Only small crossover trials have been published for angina. The metabolic anti-ischemic mechanism is biologically plausible, but the evidence base is insufficient to support strong clinical recommendations.
5d. Erectile Dysfunction
PLC plus Sildenafil in Diabetic ED (Gentile et al., 2004): To investigate the efficacy and tolerability of oral propionyl-L-carnitine (PLC) plus sildenafil in men with erectile dysfunction (ED) and diabetes unresponsive to sildenafil monotherapy, patients with medically documented ED of organic or mixed aetiology and diabetes (type 1 and 2) were randomised to receive oral PLC (2 g/day) plus sildenafil (50 mg twice weekly) (20 patients, Group 1) or sildenafil alone (20 patients, Group 2), in a double-blind, fixed-dose study. All patients had been previously treated unsuccessfully with a minimum of eight administrations of sildenafil.
ALC + PLC with Sildenafil after Prostatectomy (Cavallini et al., 2005): To determine whether PLC plus acetyl-L-carnitine (ALC) improves the effectiveness of sildenafil in restoring sexual potency after bilateral nerve-sparing radical retropubic prostatectomy, 96 patients were analyzed: 33 were given placebo, 32 used PLC 2 g/day plus ALC 2 g/day plus sildenafil 100 mg when needed, and 35 used sildenafil alone. The studied variables included sexual function assessed through the International Index of Erectile Function, peak systolic velocity and end-diastolic velocity of cavernosal arteries by dynamic echo-color Doppler, and the percentage of patients able to achieve a positive intracavernous injection test.
PLC, L-Arginine, and Nicotinic Acid with Vardenafil (Gianfrilli et al., 2009): The association of diabetes-related vascular damage and the role of metabolic factors in erectile dysfunction are well known. PLC, L-arginine, and nicotinic acid have numerous metabolic actions reported to improve endothelial function. This study investigated the administration of the combination of these three compounds alone and in association with vardenafil on endothelial function in diabetic patients with erectile dysfunction. A total of 40 patients aged between 50 and 60 years with insulin-dependent diabetes for 3β4 years were selected, and the patients were randomly subdivided into four groups of ten to be treated for 12 weeks.
Evidence strength: Preliminary to moderate. Published trials are small, often use combination formulations (making it impossible to isolate the effect of PLC alone), and are largely limited to diabetic or post-prostatectomy populations. The available data suggest potential benefit as an adjunct to PDE5 inhibitors, but stronger independent evidence is needed.
5e. Peyronie's Disease
There is evidence that carnitine is effective combined with verapamil in advanced and resistant Peyronie's disease. Cavallini et al. published a study on oral propionyl-L-carnitine and intraplaque verapamil in the therapy of advanced and resistant Peyronie's disease in BJU International 2002, volume 89, pages 895β900. Additionally, a double-blind, placebo-controlled, randomized study compared vitamin E and propionyl-L-carnitine, separately or in combination, in patients with early chronic Peyronie's disease, published in Journal of Urology 2007, volume 178, pages 1398β1403.
Evidence strength: Preliminary. Trials are small and often combine PLC with other agents such as intraplaque verapamil. No large independent RCTs exist for this indication.
5f. Diabetic Angiopathy
A method of treating peripheral vasculopathy was carried out using propionyl-L-carnitine (PLC), a propionic ester of L-carnitine. The authors evaluated in a double-blind study the efficacy of chronic oral administration of PLC versus placebo. Twenty type II diabetic patients with peripheral angiopathy were enrolled, divided into 2 groups of ten patients each. On termination of treatment, the ankle/arm pressure index, measured at rest, showed an improvement in the PLC-treated group and a deterioration in the placebo group.
Evidence strength: Preliminary. This was a small pilot trial; results are suggestive but not definitive.
5g. Wound Healing and Microvascular Endothelial Dysfunction
A preliminary study reported PLC as clinically effective in the healing of arterial or venous cutaneous chronic ulcers in 14 of 18 vasculopathic patients refractory to all other forms of therapy. The beneficial effect was associated with ameliorated blood flow recovery. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. PLC is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery.
Evidence strength: Preliminary. Only small, uncontrolled pilot studies exist for wound healing in humans. Animal data is more extensive but cannot be directly extrapolated.
5h. Ischemia-Reperfusion Injury
Animal research has provided compelling evidence that propionyl-L-carnitine administration effectively mitigates the deleterious effects of ischemia-reperfusion injury. This is substantiated by improved flap survival, diminished oxidative stress and inflammation, as well as enhanced vascularity observed in animal models. Propionyl-L-carnitine emerges as a promising therapeutic intervention to enhance tissue flap survival in reconstructive surgery, warranting further exploration through larger-scale investigations.
Evidence strength: Animal/preclinical only for the surgical flap application. Human clinical data in this specific context is lacking.
6. Body Systems and Health Areas Associated with PLC
- Cardiovascular System: Peripheral arterial disease, intermittent claudication, congestive heart failure, stable angina, and myocardial ischemia.
- Metabolic/Mitochondrial: Fatty acid oxidation, Krebs cycle anaplerosis (succinate replenishment), ATP synthesis support under hypoxic conditions.
- Vascular Endothelium: eNOS activation, nitric oxide production, reduction of oxidative stress biomarkers (ROS, NADPH oxidase), and improvement of endothelial function.
- Urogenital System: Erectile dysfunction (particularly diabetes-related or post-prostatectomy), Peyronie's disease.
- Integumentary/Wound Healing: Arterial and venous leg ulcers, cutaneous wound healing, angiogenesis.
- Renal: Studied in peripheral arterial disease patients undergoing haemodialysis.
- Skeletal Muscle: For oral administration, PLC shows that the decrease in leg muscle carnitine in PAD patients appears to correlate with poor exercise performance. The severity of the impairment in walking distance is correlated with the impairment in carnitine metabolism at the muscle level.
7. Dosage Forms and Dosages Reported in Studies
The following dosages are derived exclusively from published clinical trial reports and should not be interpreted as prescriptive recommendations:
- Peripheral Arterial Disease / Intermittent Claudication (oral): Oral propionyl-L-carnitine 1 to 3 g/day was used in double-blind multi-centre phase III studies. One trial administered 1 g three times a day orally for 90 days. 2 g daily of PLC supplementation was evaluated in a Chinese multicenter study for its ability to improve walking ability in patients with intermittent claudication.
- Congestive Heart Failure (oral): 500 mg of propionyl-L-carnitine was orally administered 3 times a day (total 1,500 mg/day) for 180 days in addition to standard treatment.
- Erectile Dysfunction (oral): Patients received oral PLC 2 g/day plus sildenafil 50 mg twice weekly in a double-blind study.
- Post-Prostatectomy ED (oral): Patients used PLC 2 g/day plus ALC 2 g/day plus sildenafil 100 mg when needed.
- Intravenous (pharmacokinetic study): Doses of 1 g, 2 g, 4 g, and 8 g were administered as a constant-rate infusion over 2 hours in a dose-escalating study.
- Phase III PAD trials (standard dose): The six phase III studies were carried out with PLC 1 g orally, twice daily.
8. Safety Considerations and Drug Interactions
General Tolerability
In a double-blind crossover trial in angina patients, no side effects were observed under propionyl-L-carnitine treatment. Across the clinical trials reviewed for intermittent claudication and heart failure, PLC was generally well tolerated. The Cochrane review and systematic meta-analyses included adverse event data as a secondary outcome.
Renal Pharmacokinetics and Saturable Reabsorption
Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC, and ALC, due to saturation of the renal tubular reabsorption process. This mechanism is relevant for patients with renal insufficiency and at high intravenous doses.
Hypothyroidism
By experiments on cells (neurons, hepatocytes, and fibroblasts) that are targets for thyroid hormones and a randomized clinical trial, L-carnitine was validated as a peripheral antagonist of thyroid hormone action. In particular, L-carnitine inhibits both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei. This is relevant because thyroid hormone action is mainly mediated by specific nuclear receptors. There is a concern that propionyl-L-carnitine might make hypothyroidism worse or thyroid hormone treatment less effective. Accordingly, individuals with hypothyroidism are cautioned against its use.
Seizure Susceptibility
Some people who have a history of seizures have reported an increase in the number and severity of seizures after taking L-carnitine by mouth or intravenously (by IV). There is a concern that this might also occur with propionyl-L-carnitine, because it is a similar chemical.
Anticoagulant Interactions
Acenocoumarol is used to slow blood clotting. Propionyl-L-carnitine might increase the effects of acenocoumarol, which might increase the chances of bruising and bleeding. Warfarin is used to slow blood clotting. Propionyl-L-carnitine might increase the effects of warfarin and increase the chances of bruising and bleeding. Blood checks are warranted, and the dose of warfarin might need to be changed.
D-Carnitine Interference
D-carnitine might interfere with the way the body processes L-carnitine, which is a "parent" chemical for propionyl-L-carnitine. Taking D-carnitine might cause propionyl-L-carnitine levels to drop too low.
Thyroid Hormone Medications
Propionyl-L-carnitine might decrease how well thyroid hormone works in the body. Taking propionyl-L-carnitine with thyroid hormone might decrease the effects of thyroid hormones.
Pregnancy and Breastfeeding
There is insufficient reliable information to know whether propionyl-L-carnitine is safe to use when pregnant or breastfeeding.
Evidence Gaps and Limitations
The totality of the clinical evidence on PLC has several important limitations that must be acknowledged. Many trials were funded or conducted by pharmaceutical interests (particularly the Italian company Sigma-Tau, which held the principal patents on PLC formulations). Many individual studies are small and underpowered. Results from clinical trials have been inconsistent. All but one of the studies included in the Cochrane review were studies on the efficacy of PLC versus placebo. More research with this medication could be done, such as head-to-head comparisons with other vasoactive drugs. It is not clear whether the benefits of propionyl-L-carnitine and other carnitine derivatives are the same as those of L-carnitine itself, as the parent compound from which PLC is derived.
References
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