In this chronic mouse asthma model, L-Carnitine ((R)-Carnitine) (125, 250 mg/kg; ip) had lower urinary LTE4 excretion and more dramatic bronchodilation [2].

Absorption, Distribution and Excretion
The absolute bioavailability is 15% (tablets or solution). The time to peak concentration is 3.3 hours. Following a single intravenous administration, 73.1 ± 16% of the dose is excreted in the urine within 0–24 hours. With oral carnitine supplementation and a high-carnitine diet, 58–65% of the administered radioactive dose is recovered from urine and feces within 5–11 days. The steady-state volume of distribution (Vss, above endogenous baseline) for the intravenously administered dose is calculated to be 29.0 ± 7.1 L. However, this value is expected to underestimate the actual steady-state volume of distribution (Vss). The average total clearance is 4 L/h. L-carnitine is a natural compound that promotes the entry of fatty acids into mitochondria for β-oxidation. ...In the human body, the endogenous carnitine pool consists of free L-carnitine and a series of short-chain, medium-chain, and long-chain esters. Its maintenance pathways include absorption of L-carnitine from the diet, biosynthesis in the body, and significant reabsorption by the renal tubules from glomerular filtrate. Furthermore, carrier-mediated transport ensures a high tissue/plasma concentration ratio in tissues highly dependent on fatty acid oxidation. After oral administration of L-carnitine, absorption is partly via carrier-mediated transport and partly via passive diffusion. The absolute bioavailability after oral administration of 1-6 grams is 5-18%. In contrast, the bioavailability of dietary L-carnitine can be as high as 75%. Therefore, the absorption efficiency of pharmacological doses or supplemental doses of L-carnitine is lower than the relatively small amounts found in a normal diet. L-carnitine and its short-chain esters do not bind to plasma proteins; although L-carnitine is present in blood cells, its distribution in whole blood between erythrocytes and plasma is extremely slow. Following intravenous injection, the initial volume of distribution of L-carnitine is typically approximately 0.2–0.3 L/kg, equivalent to the volume of extracellular fluid. L-carnitine has at least three distinct pharmacokinetic compartments, with the slowest equilibrium compartment consisting of skeletal and cardiac muscle. L-carnitine is primarily excreted via urine. Under baseline conditions, the renal clearance of L-carnitine (1–3 mL/min) is significantly lower than the glomerular filtration rate (GFR), indicating extensive (98–99%) tubular reabsorption. The threshold concentration for tubular reabsorption (beyond which reabsorption begins to decline) is approximately 40–60 μmol/L, similar to endogenous plasma L-carnitine levels. Therefore, following exogenous administration, renal clearance of L-carnitine increases, approaching GFR after high-dose intravenous injection. …In mammals, the carnitine pool consists of non-esterified L-carnitine and various acylcarnitine esters. Among these esters, acetyl-L-carnitine is the most important in both quantity and function. The maintenance of carnitine homeostasis depends on dietary absorption, adequate synthesis, and efficient renal reabsorption. Dietary L-carnitine is absorbed via active and passive transport across the intestinal cell membrane. The bioavailability of dietary L-carnitine is 54-87%, depending on the amount of L-carnitine in the diet. Absorption of L-carnitine dietary supplements (0.5-6 g) is primarily passive transport, with a bioavailability of 14-18% of the dose. Unabsorbed L-carnitine is mainly degraded by microorganisms in the large intestine. Circulating L-carnitine is distributed in two kinetically defined compartments: one large and slow-turning (presumably muscle), and the other relatively small and fast-turning (presumably liver, kidneys, and other tissues). Under normal dietary L-carnitine intake, the systemic turnover time is 38-119 hours. In vitro studies have shown that acetyl-L-carnitine undergoes partial hydrolysis within intestinal cells during absorption. In vivo studies showed that oral supplementation with acetyl-L-carnitine 2 g/day increased circulating acetyl-L-carnitine concentration by 43%, suggesting that acetyl-L-carnitine was at least partially absorbed without hydrolysis. Following a single intravenous injection (0.5 g), acetyl-L-carnitine was rapidly hydrolyzed, but not completely; both acetyl-L-carnitine and L-carnitine concentrations returned to baseline levels within 12 hours. At normal circulating L-carnitine concentrations, renal reabsorption of L-carnitine is highly efficient (90-99% of filtration load; clearance 1-3 mL/min), but its kinetics exhibit saturation. Therefore, with increasing circulating L-carnitine concentrations (e.g., after high-dose intravenous or oral L-carnitine injections), reabsorption efficiency decreases and clearance increases, leading to a rapid decline in circulating L-carnitine concentration to baseline levels. The elimination kinetics of acetyl-L-carnitine are similar to those of L-carnitine. There is evidence that both L-carnitine and acetyl-L-carnitine are secreted via renal tubules. ...
This study investigated the pharmacokinetics of L-carnitine and its metabolites in seven healthy subjects. Subjects received oral doses of 0, 0.5, 1, and 2 g of L-carnitine three times daily for seven days. Within an 8-hour dosing interval, the mean plasma concentration of L-carnitine significantly increased from baseline (54.2 ± 9.3 μM, P < 0.05), reaching 80.5 ± 12.5 μM after a 0.5 g dose; no further increase was observed at higher doses. Renal clearance of L-carnitine was significantly increased (P < 0.001), indicating that renal tubular reabsorption had reached saturation. Plasma levels of trimethylamine increased proportionally with increasing L-carnitine dose, but renal clearance remained unchanged. At only a 2 g dose of L-carnitine, plasma concentrations of trimethylamine-N-oxide were significantly increased from baseline (from 34.5 ± 2.0 μM to 149 ± 145 μM), and renal clearance decreased with increasing dose (P < 0.05). There was no evidence of a nonlinear process in the metabolism of trimethylamine to trimethylamine-N-oxide. In summary, the pharmacokinetics of oral L-carnitine are nonlinear at doses above 0.5 g three times daily. Evidence suggests that L-carnitine is absorbed in the intestine via a combination of active transport and passive diffusion. Reported bioavailability after oral administration varies widely, ranging from estimates as low as 16% to 18% to as high as 54% to 87%... Mucosal absorption of carnitine appears to saturate at a dose of approximately 2 g. Peak plasma concentrations are reached approximately 3.5 hours after oral administration, followed by a slow decline, with a half-life of approximately 15 hours. Carnitine is primarily excreted by the kidneys. The heart, skeletal muscle, liver, kidneys, and epididymis possess specific carnitine transport systems that concentrate carnitine in these tissues. Although there is evidence of increased levels of free carnitine and its metabolites in blood and urine after oral administration, no significant changes in erythrocyte carnitine levels have been observed in healthy subjects, suggesting a slower rate of tissue replenishment of carnitine after oral administration, or a lower capacity for carnitine transport to tissues under normal conditions. For more complete data on the absorption, distribution, and excretion of L-carnitine (11 items in total), please visit the HSDB records page. Metabolites/Metabolites After oral administration, unabsorbed L-carnitine is metabolized by bacterial flora in the gastrointestinal tract. Major metabolites include trimethylamine N-oxide and [3H]-γ-butylbetaine. In mammals, L-carnitine is synthesized from ε-N-trimethyllysine, which originates from post-translational methylated lysine residues in proteins and protein turnover. In normal individuals, the estimated rate of L-carnitine synthesis is approximately 1.2 μmol/kg/day. The biosynthetic rate of L-carnitine is regulated by the availability of ε-N-trimethyllysine. Therefore, conditions that increase protein methylation and/or protein turnover may increase the biosynthetic rate of L-carnitine. Carnitine synthesis begins with the methylation of the amino acid L-lysine by S-adenosylmethionine (SAMe). Magnesium, vitamin C, iron, vitamins B3 and B6, and α-ketoglutarate—as well as cofactors responsible for SAMe synthesis (methionine, folic acid, vitamin B12, and betaine)—are all essential for endogenous carnitine synthesis. Unabsorbed L-carnitine is degraded by microorganisms in the large intestine. The major metabolites identified are trimethylamine oxide in urine and γ-butyl betaine in feces. Carnitine plays an indispensable role in fatty acid oxidation. Previous studies have shown that fetal carnitine originates from the mother and is transported through the placenta. Recent studies have confirmed the existence and important role of an active fatty acid oxidation system in the human placenta and fetus. In light of these findings… this study investigated carnitine metabolism in the placental-fetal unit by measuring the activities of carnitine metabolites, intermediate metabolites of carnitine biosynthesis, and carnitine biosynthetic enzymes in human full-term placenta, umbilical cord blood, and selected embryonic and fetal tissues (5–20 weeks of gestation). Although low, the activity of γ-butylbetaine dioxygenase was detectable in the placenta. This enzyme, previously thought to be expressed only in the kidneys, liver, and brain, catalyzes the final step in the carnitine biosynthesis pathway. Furthermore,… the kidneys, liver, and spinal cord of the human fetus are already capable of synthesizing carnitine. The ability of the placenta and fetus to synthesize carnitine suggests that, given limited maternal carnitine supply, carnitine biosynthesis in the placental-fetal unit may provide sufficient carnitine for placental and fetal metabolism. /Carnitine/
For more complete data on the metabolism/metabolites of L-carnitine (7 metabolites), please visit the HSDB record page.
After oral administration, unabsorbed L-carnitine is metabolized by bacterial flora in the gastrointestinal tract. Major metabolites include trimethylamine N-oxide and [3H]-γ-butylbetaine.
Excretion route: Following a single intravenous injection, 73.1 ± 16% of the dose is excreted in the urine within 0–24 hours.
After oral carnitine supplementation combined with a high-carnitine diet, 58–65% of the radioactive dose is recovered in urine and feces within 5–11 days.
Half-life: 17.4 hours after a single intravenous administration (elimination).
Biobiological half-life
17.4 hours after a single intravenous administration (elimination).
Distribution: 0.585 hours; Elimination: 17.4 hours
……Half-life in blood is approximately 15 hours……

Toxicity Summary
L-carnitine can be synthesized in the body from the amino acids lysine or methionine. Vitamin C (ascorbic acid) is essential for carnitine synthesis. L-carnitine is a carrier molecule for the transport of long-chain fatty acids across the inner mitochondrial membrane. It can also excrete them from subcellular organelles and cells into the urine before the acyl groups accumulate to toxic concentrations. Only L-carnitine (sometimes called vitamin BT) affects lipid metabolism. L-carnitine is metabolized by a variety of proteins through different pathways, including carnitine transporters, carnitine translocases, carnitine acetyltransferases, and carnitine palmitoyltransferases. Protein Binding No Toxicity Data LD50 > 8 g/kg (mice, oral). Interactions …This study aimed to investigate whether supplementation with L-carnitine, combined with dietary-induced increases in circulating insulin levels, could improve systemic carnitine retention. In two randomized visits (Study A), eight male subjects ingested 3 grams of L-carnitine daily, followed by four 500 ml solutions, each containing either flavored water (Con) or 94 grams of monosaccharide (glucose syrup; CHO). Conversely, 14 male subjects ingested 3 grams of L-carnitine daily, followed by two weeks of either 500 ml of the control group (Con) or the carbohydrate group (CHO) (Study B). In Study A, the area under the curve (AUC) of serum insulin in the carbohydrate intake group was four times higher than that in the control group (P < 0.001), and plasma total cholesterol (TC) concentrations were lower throughout the carbohydrate intake period (P < 0.05). In Study A, the 24-hour urinary TC excretion in the carbohydrate intake group was lower than that in the control group (155.0 ± 10.7 mg vs. 212.1 ± 17.2 mg; P < 0.05). In Study B, daily urinary total cholesterol (TC) excretion increased after 3 days (from 65.9 ± 18.0 mg to 281.0 ± 35.0 mg; P < 0.001) and remained at a high level throughout the control trial. During the CHO trial, daily urinary TC excretion increased from a similar baseline of 53.8 ± 9.2 mg to 166.8 ± 17.3 mg after 3 days (P < 0.01), lower than the excretion during the Con trial (P < 0.01), and remained at a low level throughout the study (P < 0.001). The difference in plasma TC concentration in Study A compared to 24-hour urinary TC excretion in both studies suggests that insulin enhanced carnitine retention in the CHO trial. ...The effects of the anticancer drug carboplatin on plasma L-carnitine (LC) and its main ester, acetyl-L-carnitine (ALC), concentrations and urinary excretion in cancer patients were investigated. Carboplatin treatment was associated with a significant reduction in urinary L-carnitine (LC) and L-carnitine (ALC), likely due to inhibition of renal carnitine reabsorption. Rats were divided into four groups: Group 1, control group (0.9% sodium chloride solution); Group 2, intravenous doxorubicin (DOX, 7.5 mg/kg); Group 3, DOX combined with low-dose (40 mg/kg) L-carnitine; and Group 4, DOX combined with high-dose (200 mg/kg) L-carnitine. L-carnitine was administered 1 hour before doxorubicin injection and then daily for 15 days. Rats in Group 2 exhibited hypoalbuminemia, hyperlipidemia, increased urinary protein excretion, and elevated plasma creatinine and blood urea nitrogen. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) decreased with increasing renal vascular resistance (RVR). Renal catalase (CAT) activity was decreased. Plasma triglyceride and cholesterol levels decreased in groups 3 and 4. L-carnitine improved renal function by increasing GFR and ERPF and decreasing plasma creatinine and urea nitrogen levels. Renal CAT activity was significantly increased in groups 3 and 4 compared to group 2. Histopathological results showed glomerular capillary dilation and tubular dilation in group 2 rats. The lesions in groups 3 and 4 rats were milder… Recent literature reports no cases of allergic reactions or serious side effects after L-carnitine treatment in patients with acute valproic acid intake. Other studies have shown that L-carnitine can improve the survival rate of patients with valproic acid-induced hepatotoxicity. Early intravenous administration of L-carnitine, rather than enteral administration, was associated with the highest liver survival rate. Individual pediatric case reports suggest that carnitine administration may reverse toxic metabolic pathways but may not accelerate the improvement of clinical symptoms. …/Carnitine/
For more complete data on interactions of L-carnitine (17 in total), please visit the HSDB record page.

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Non-human toxicity values
Rat intravenous LD50: 5.4 g/kg
Mouse oral LD50: 19.2 g/kg

[1]. Agarwal A, et al. Role of L-carnitine in female infertility. eprod Biol Endocrinol. 2018 Jan 26;16(1):5.
[2]. Ferreira GC, et al. L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res. 2017 Jun;42(6):1661-1675.
[3]. Uzuner N, et al. The role of L-carnitine in treatment of a murine model of asthma. Acta Med Okayama. 2002 Dec;56(6):295-301.

Therapeutic Uses
L-carnitine is indicated for the treatment of primary systemic carnitine deficiency (a genetically determined impairment of the ability to synthesize or utilize L-carnitine normally from dietary sources) or secondary carnitine deficiency caused by congenital metabolic defects. /Included on US product label/
L-carnitine for injection is indicated for the prevention and treatment of carnitine deficiency in patients with end-stage renal disease receiving hemodialysis support. /Included on US product label/
L-carnitine oral solution is indicated for the prevention and treatment of secondary carnitine deficiency caused by valproic acid poisoning. /Not included on US product label/
L-carnitine, acetyl-L-carnitine, and/or propionyl-L-carnitine may be used as replacement therapy to restore normal carnitine concentrations and/or a normal ratio of non-esterified to esterified carnitine… For primary and certain secondary carnitine deficiencies… L-carnitine is used as replacement therapy.
For more complete data on the therapeutic uses of L-carnitine (29 in total), please visit the HSDB record page.

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Drug Warnings
Various mild gastrointestinal discomforts have been reported during long-term oral administration of L-carnitine or D,L-carnitine; these discomforts include transient nausea and vomiting, abdominal cramps, and diarrhea. Mild myasthenia gravis has only been reported in uremic patients receiving D,L-carnitine treatment. Gastrointestinal adverse reactions can be avoided by slow administration or by increasing the dilution when taking liquid cannibalistic (levocarnitine) oral solution or cannibalistic SF (levocarnitine) sugar-free oral solution. Reducing the dose usually reduces or eliminates drug-related body odor or gastrointestinal symptoms (if any). Tolerance should be closely monitored during the first week of treatment and after any dose increase. Seizures have been reported in patients receiving oral or intravenous levocarnitine (regardless of a history of epilepsy). Increased frequency and/or severity of seizures have been reported in patients with a history of epilepsy. Six patients with end-stage renal disease undergoing hemodialysis three times a week were given 1 gram of levocarnitine orally daily for 12 days. Predialysis plasma L-carnitine concentration (mean ± standard deviation) significantly increased from day 1 (baseline; 32.4 ± 6.1 μM) (P < 0.05) to day 8 (66.1 ± 13.8 μM), then remained stable. Although plasma trimethylamine levels remained constant, predialysis plasma trimethylamine-N-oxide concentration significantly increased from day 1 (289.1 ± 236.1 μM) (P < 0.05) to day 12 (529.0 ± 237.9 μM). The hemodialysis clearance rates of L-carnitine, trimethylamine, and trimethylamine-N-oxide were 14.3 ± 8.2 L/h, 14.1 ± 10.6 L/h, and 12.4 ± 5.4 L/h, respectively, indicating their effective removal by dialysis. For end-stage renal disease patients undergoing hemodialysis, daily oral administration of 1 gram of L-carnitine can raise plasma concentrations to physiological levels. However, given the persistently elevated plasma trimethylamine-N-oxide concentration, which nearly doubled within two weeks, concerns remain regarding the potential adverse consequences of this dosing regimen. ...In patients with primary carnitine deficiency, the kidneys exhibit abnormalities in the processing of L-carnitine and/or its transport to muscle tissue. Similarly, many secondary carnitine deficiencies, including some drug-induced conditions, are due to impaired renal tubular reabsorption. End-stage renal disease patients undergoing dialysis may develop secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyzer... Our aim was to examine the effects of L-carnitine supplementation on secondary hyperparathyroidism and bone metabolism in hemodialysis patients in a randomized study. This study observed 83 patients undergoing chronic hemodialysis; 44 received intravenous L-carnitine (15 mg/kg) after each hemodialysis session for 6 months, while the remaining 39 received a placebo. The levels of free carnitine (CAR), calcium (Ca), inorganic phosphate (P), calcium-phosphorus product, parathyroid hormone (PTH), bone-specific alkaline phosphatase (β-ALP), osteocalcin (OC), and osteoprotegerin (OPG) were monitored. Compared with pre-treatment levels, some parameters changed at 6 months in the L-carnitine supplementation group (data are presented as median; NS indicates no statistical significance): PTH, 186.0 vs. 135.5 ng/L (NS); β-ALP, 13.9 vs. 13.2 ug/L (P < 0.05); OC, 78.3 vs. 68.8 ug/L (NS). The OPG level in the treatment group was 144.0 ng/L, and in the control group it was 182.0 ng/L (P < 0.05). The changes in PTH levels in the control group were as follows: PTH level was 148.0 ng/L, compared to 207.0 ng/L in the control group (no statistical significance); β-ALP level was 15.2 ug/L, compared to 13.2 ug/L in the control group (P < 0.05); OC level was 62.7 ug/L, compared to 79.8 ug/L in the control group (P < 0.05); OPG level was 140.0 ng/L, compared to 164.0 ng/L in the control group (no statistical significance). In patients supplemented with L-carnitine, changes in CAR and OPG were significantly correlated (r = 0.51, P < 0.001). L-carnitine supplementation led to a significant increase in serum OPG concentration. However, compared to the control group, only a non-significant trend of improvement in secondary hyperparathyroidism and a decrease in bone turnover rate was observed in hemodialysis patients supplemented with L-carnitine. Currently, the use of L-carnitine appears to be unreasonable. For more complete data on drug warnings regarding L-carnitine (9 in total), please visit the HSDB record page.

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Pharmacodynamics
L-carnitine is a carrier molecule for the transport of long-chain fatty acids across the inner mitochondrial membrane. It also removes acyl groups from subcellular organelles and cells into the urine, preventing their accumulation to toxic concentrations. Carnitine deficiency can lead to liver, heart, and muscle problems. The biochemical definition of carnitine deficiency is an abnormally low plasma free carnitine concentration, below 20 μmol/L one week after birth, and may be accompanied by low carnitine concentrations in tissues and/or urine. Furthermore, this condition may be associated with a plasma acylcarnitine/L-carnitine ratio greater than 0.4 or an abnormally high urinary acylcarnitine concentration. Only L-carnitine (sometimes called vitamin BT) affects lipid metabolism. “Vitamin BT” actually contains D,L-carnitine, which competitively inhibits L-carnitine, leading to deficiency. L-carnitine can be used for treatment, such as stimulating gastric and pancreatic juice secretion and treating hyperlipoproteinemia.

C7H15NO3

161.201

161.105

541-15-1

10917

White, crystalline, hygroscopic powder

197-212 °C(lit.)

-32 ° (C=1, H2O)

-4.52

1

3

3

11

134

1

O([H])[C@]([H])(C([H])([H])C(=O)[O-])C([H])([H])[N+](C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]

PHIQHXFUZVPYII-ZCFIWIBFSA-N

InChI=1S/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3/t6-/m1/s1

(3R)-3-hydroxy-4-(trimethylazaniumyl)butanoate

L-Cartin; Carnitor; Levocarnitine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 50 mg/mL (~310.17 mM)

Solubility in Formulation 1: 100 mg/mL (620.35 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)