kinetics, pharmacokinetics, and regulation of l-carnitine ...€¦ · kinetics, pharmacokinetics,...
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![Page 1: Kinetics, Pharmacokinetics, and Regulation of L-Carnitine ...€¦ · Kinetics, Pharmacokinetics, and Regulation of L-Carnitine and Acetyl-L-carnitine Metabolism Charles J. Rebouche,](https://reader034.vdocuments.site/reader034/viewer/2022051807/6008a0fbfc01f721192db87e/html5/thumbnails/1.jpg)
Kinetics, Kinetics, PharmacokineticsPharmacokinetics, and , and Regulation of LRegulation of L--CarnitineCarnitine and and AcetylAcetyl--LL--carnitinecarnitine MetabolismMetabolism
Charles J.Charles J. ReboucheRebouche, Ph.D., Ph.D.
![Page 2: Kinetics, Pharmacokinetics, and Regulation of L-Carnitine ...€¦ · Kinetics, Pharmacokinetics, and Regulation of L-Carnitine and Acetyl-L-carnitine Metabolism Charles J. Rebouche,](https://reader034.vdocuments.site/reader034/viewer/2022051807/6008a0fbfc01f721192db87e/html5/thumbnails/2.jpg)
Fecal Excretion
Small Intestine
Extracellular Fluid
Diet Large Intestine
Microbial Degradation
Kidney Kidney
Other TissuesOther TissuesLiverLiver
Synthesis
Reabsorption
Urinary Excretion
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Carrier-mediated and Passive
Passive Transcellular
Passive Paracellular
Carnitine + Acetyl-CoA
Acetylcarnitine + CoA
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Absorption of Dietary LAbsorption of Dietary L--CarnitineCarnitine
Data from: Rebouche & Chenard (1991) J Nutr 121:539-546
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Metabolism of LMetabolism of L--Carnitine in Carnitine in the Large Intestinethe Large Intestine
L-Carnitine
Crotonobetaine
γ-Butyrobetaine
Trimethylamine
Trimethylamine OxideLiver
Feces Urine
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Carnitine Kinetics in HumansCarnitine Kinetics in Humans
Data from: Rebouche & Engel (1984) J Clin Invest 73, 857-867
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A Kinetic Model for Carnitine Metabolism A Kinetic Model for Carnitine Metabolism in Humansin Humans
Endogenous synthesis Absorbed from diet
Kab = 0.005Kca = 0.30Qc3.1 mmol
Qa0.81 mmol
Qb84
mmolKba = 0.52Kac = 0.087
Koa = 0.071
Urinary Excretion
Data from: Rebouche & Engel (1984) J Clin Invest 73, 857-867
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Renal Carnitine ExcretionRenal Carnitine ExcretionOpen symbols:baseline; no infusion
Closed symbols:carnitine infusion
Circles:omnivores
Triangles:vegans
Data from: Rebouche, et al. (1993) Am J Clin Nutr 58:660-665
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Diet SupplementFecal
ExcretionSmall Intestine
Extracellular Fluid
Diet Large Intestine
Microbial Degradation
Kidney Kidney
Other TissuesOther TissuesLiverLiver
Urinary Excretion
Synthesis
Reabsorption
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Bioavailability of Oral Carnitine Bioavailability of Oral Carnitine SupplementsSupplements
Dose Bioavailability Reference
2 g 0.16 Harper et al., 1988
6 g* 0.05 Harper et al., 1988
30 and 100 mg/kg 0.16, 0.14 Rizza et al., 1992
100 mg/kg 0.18 Segre et al., 1988
2 g every 12 h 0.14 - 0.16 Sahajwalla et al., 1995
600 mg, 3times/day
0.17 Rebouche, 1991
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Kinetic Parameters for Oral Carnitine Kinetic Parameters for Oral Carnitine SupplementsSupplements
Dose Tmax T1/2 Reference
(h) (h)
2 g 4.9 6.5 Harper et al., 1988
30 mg/kg 5.2 1.9 Segre et al., 1988
100 mg/kg 3.7 Segre et al., 1988
30 mg/kg 3.0 3.0 Rizza et al., 1992
100 mg/kg 3.5 4.1 Rizza et al., 1992
2 g 3.1-3.4 Sahajwalla et al., 1995
600 mg 4.0 Rebouche, 1991
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Serum Response to Multiple Oral Serum Response to Multiple Oral DosingDosing
Open circles -8 am sample
Filled circles -6 pm sample
Blue circles -carnitine supplement
Red circles -no supplement
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Carnitine Supplement in RatsCarnitine Supplement in Rats
Data from: Rebouche (1983) J Nutr 113:1906-1913
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Carnitine Supplement and Carnitine Supplement and Acylcarnitine Ester AppearanceAcylcarnitine Ester Appearance
• Serum acylcarnitine ester concentrationsno supplement 7.27 µmol/Lsupplement 13.9 µmol/L
• Acylcarnitine ester excretionno supplement 3.27 µmol/kg/daysupplement 6.06 µmol/kg/day
• Ratio, non-esterified carnitine/total carnitine in urineno supplement 0.58supplement 0.62
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AcetylAcetyl--LL--carnitine carnitine IV IV PharmacokineticsPharmacokinetics
Time (h)
Acetyl-L-carnitine HCl 500 mg i.v. in healthy volunteers
Plas
ma
Con
cent
ratio
n (µ
mol
/L)
Data from: Marzo et al. (1989) Eur J Clin Pharmacol 37:59-63
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AcetylAcetyl--LL--carnitine carnitine and Land L--Carnitine Carnitine Clearance and Clearance and InterconversionsInterconversions
“Clearances of Transformation”Renal Clearance
Sex Basal 0-12h
12-24h
CLALC-LC CLLC-ALC
L/h L/hCLALC F 0.57 1.40 1.23 Females 14.1 2.48
M 0.35 2.08 0.64 Males 9.04 1.41
CLLC F 0.14 1.46 0.39
M 0.24 3.42 0.34
Data from: Marzo et al. (1989) Eur J Clin Pharmacol 37:59-63
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Future Research DirectionsFuture Research Directions
• Do benefits of oral L-carnitine supplements accrue from increase of intracellular carnitine concentrations, or from increased IC/EC carnitine-acylcarnitine exchange?
• Acetyl-L-carnitine supplements: Where do the acetyl and carnitine moieties go, and how much goes intact (as acetyl-L-carnitine)?
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Summary and HighlightsSummary and Highlights• Dietary carnitine is absorbed by active transport and diffusion
processes, whereas supplements are absorbed primarily by diffusion. Intracellular acetylation plays a role in the absorption process.
• Renal excretion/reabsorption provides driving force for homeostatic regulation of carnitine metabolism.
• Rapid carnitine-carnitine and carnitine-acylcarnitine ester exchange occurs between tissues and extracellular compartment.
• Repeated dosing L-carnitine supplements are capable of maintaining increased circulating and probably tissue carnitine concentrations.
• Acetyl-L-carnitine supplements are rapidly deacetylated.