RESUMEN
The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double-blind clinical study, participants chewed caffeine (n = 12) or placebo (n = 12) gum for 5 minutes at 2-hour intervals over a 6-hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine.
Asunto(s)
Cafeína , Calcio , Adulto , Cafeína/efectos adversos , Creatinina , Humanos , Pruebas de Función Renal , SodioRESUMEN
BACKGROUND: Anaemia is a common complication associated with haemodialysis and is usually managed by treatment with recombinant human erythropoietin (rHuEPO). However, many patients remain hyporesponsive to rHuEPO treatment despite adequate iron therapy. The effect of L-carnitine administration on rHuEPO dose and/or haematocrit in haemodialysis patients has been previously reported with equivocal results. This study examined the relationship between endogenous carnitine pool composition and rHuEPO requirements in long-term haemodialysis patients. METHODS: Pre-dialysis blood samples were collected from 87 patients and analysed for plasma L-carnitine and individual acylcarnitine levels by LCMS/MS. As an indication of rHuEPO responsiveness, erythropoietin resistance index (ERI) was calculated as rHuEPO dose/kg/week normalized for haemoglobin levels. RESULTS: A significant negative correlation between L-carnitine levels and ERI was found (P = 0.0421). All patients categorized as high ERI (>0.02 microg/kg/week/gHb) exhibited subnormal L-carnitine levels (<30 microM); conversely, patients with normal L-carnitine levels (>30 microM) displayed low ERI values (<0.02 microg/kg/week/gHb). More importantly, the ratio of non-acetyl acylcarnitines/total carnitine was significantly positively correlated with ERI (P = 0.0062). CONCLUSIONS: These data illustrate the relationship between carnitine levels and response to rHuEPO treatment in haemodialysis patients, in particular, the importance of the proportion of long-chain acylcarnitines within the plasma carnitine pool. This proportion may be more indicative of the response to L-carnitine supplementation than absolute L-carnitine levels alone.
Asunto(s)
Anemia/tratamiento farmacológico , Carnitina/sangre , Eritropoyetina/uso terapéutico , Fallo Renal Crónico/sangre , Fallo Renal Crónico/terapia , Diálisis Renal , Adulto , Anciano , Anemia/sangre , Anemia/etiología , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Diálisis Renal/efectos adversosRESUMEN
It has been widely established that patients with end-stage renal disease undergoing chronic haemodialysis therapy exhibit low endogenous levels of L-carnitine and elevated acylcarnitine levels; however, the clinical implication of this altered carnitine profile is not as clear. It has been suggested that these disturbances in carnitine homeostasis may be associated with a number of clinical problems common in this patient population, including erythropoietin-resistant anaemia, cardiac dysfunction, and dialytic complications such as hypotension, cramps and fatigue. In January 2003, the Centers for Medicare and Medicaid Services (USA) implemented coverage of intravenous L-carnitine for the treatment of erythropoietin-resistant anaemia and/or intradialytic hypotension in patients with low endogenous L-carnitine concentrations. It has been estimated that in the period of 1998-2003, 3.8-7.2% of all haemodialysis patients in the USA received at least one dose of L-carnitine, with 2.7-5.2% of patients receiving at least 3 months of supplementation for one or both of these conditions. The use of L-carnitine within Australia is virtually non-existent, which leads us to the question: Are Australian haemodialysis patients missing out? This review examines the previous research associated with L-carnitine administration to chronic dialysis patients for the treatment of anaemia, cardiac dysfunction, dyslipidaemia and/or dialytic symptoms, and discusses whether supplementation is warranted within the Australian setting.
Asunto(s)
Anemia/tratamiento farmacológico , Ácido Ascórbico/farmacocinética , Carnitina/uso terapéutico , Fallo Renal Crónico/terapia , Diálisis Renal , Complejo Vitamínico B/uso terapéutico , Vitaminas/farmacocinética , Anemia/epidemiología , Anemia/etiología , Ácido Ascórbico/uso terapéutico , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/epidemiología , Prevalencia , Australia del Sur/epidemiología , Resultado del Tratamiento , Vitaminas/uso terapéutico , Australia Occidental/epidemiologíaRESUMEN
AIMS: Patients requiring chronic haemodialysis may develop a secondary carnitine deficiency through dialytic loss of L-carnitine. A previous report has described the plasma concentrations of L-carnitine in 12 such patients under baseline conditions and after L-carnitine administration (20 mg kg(-1)). A three-compartment pharmacokinetic model was developed to describe these data to make inferences about carnitine supplementation in these patients. METHODS: L-carnitine removal was mediated solely by intermittent haemodialysis, which was incorporated into the model as an experimentally derived dialysis clearance value that was linked to an on-off pulse function. Data were described by a model with a central compartment linked to 'fast'- and 'slow'-equilibrating peripheral compartments. RESULTS: The model adequately described the changing plasma concentrations of endogenous L-carnitine in individual haemodialysis patients. Based on pooled data (mean +/- SD; n = 12), the volume of the central compartment was 10.09 +/- 0.72 l and the transfer rate constants into and out of the slowly equilibrating pool were 0.100 +/- 0.018 h(-1) and 0.00014 +/- 0.00016 h(-1), respectively. The turnover time of L-carnitine in the slow pool (which was assumed to represent muscle) was approximately 300 days. The model was in general agreement with separate data on the measured loss of carnitine from muscle in dialysis patients. CONCLUSIONS: Haemodialysis causes rapid reductions in plasma L-carnitine concentrations with each dialysis session. Plasma concentrations are restored between sessions by redistribution from peripheral compartments. However, during chronic haemodialysis, the ongoing dialytic loss of L-carnitine may lead to a slow depletion of the compound, contributing to a possible secondary deficiency.
Asunto(s)
Carnitina/farmacocinética , Fallo Renal Crónico/metabolismo , Modelos Biológicos , Diálisis Renal/efectos adversos , Australia , Carnitina/administración & dosificación , Carnitina/sangre , Femenino , Humanos , Inyecciones Intravenosas , Fallo Renal Crónico/terapia , Masculino , Tasa de Depuración MetabólicaRESUMEN
L-Carnitine is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for beta-oxidation. Exogenous L-carnitine is used clinically for the treatment of carnitine deficiency disorders and a range of other conditions. In humans, the endogenous carnitine pool, which comprises free L-carnitine and a range of short-, medium- and long-chain esters, is maintained by absorption of L-carnitine from dietary sources, biosynthesis within the body and extensive renal tubular reabsorption from glomerular filtrate. In addition, carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation. The absorption of L-carnitine after oral administration occurs partly via carrier-mediated transport and partly by passive diffusion. After oral doses of 1-6g, the absolute bioavailability is 5-18%. In contrast, the bioavailability of dietary L-carnitine may be as high as 75%. Therefore, pharmacological or supplemental doses of L-carnitine are absorbed less efficiently than the relatively smaller amounts present within a normal diet.L-Carnitine and its short-chain esters do not bind to plasma proteins and, although blood cells contain L-carnitine, the rate of distribution between erythrocytes and plasma is extremely slow in whole blood. After intravenous administration, the initial distribution volume of L-carnitine is typically about 0.2-0.3 L/kg, which corresponds to extracellular fluid volume. There are at least three distinct pharmacokinetic compartments for L-carnitine, with the slowest equilibrating pool comprising skeletal and cardiac muscle.L-Carnitine is eliminated from the body mainly via urinary excretion. Under baseline conditions, the renal clearance of L-carnitine (1-3 mL/min) is substantially less than glomerular filtration rate (GFR), indicating extensive (98-99%) tubular reabsorption. The threshold concentration for tubular reabsorption (above which the fractional reabsorption begins to decline) is about 40-60 micromol/L, which is similar to the endogenous plasma L-carnitine level. Therefore, the renal clearance of L-carnitine increases after exogenous administration, approaching GFR after high intravenous doses. Patients with primary carnitine deficiency display alterations in the renal handling of L-carnitine and/or the transport of the compound into muscle tissue. Similarly, many forms of secondary carnitine deficiency, including some drug-induced disorders, arise from impaired renal tubular reabsorption. Patients with end-stage renal disease undergoing dialysis can develop a secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyser, and L-carnitine has been used for treatment of some patients during long-term haemodialysis. Recent studies have started to shed light on the pharmacokinetics of L-carnitine when used in haemodialysis patients.
Asunto(s)
Carnitina/farmacocinética , Administración Oral , Carnitina/administración & dosificación , Carnitina/biosíntesis , Humanos , Inyecciones Intravenosas , Tasa de Depuración Metabólica/fisiologíaRESUMEN
This study examines the potential for the phytoestrogenic isoflavones, a type of complementary medicine, to be involved in pharmacokinetic interactions in the liver. Rat livers were isolated and perfused to steady state, in single-pass mode, with either 5 microM paracetamol (n = 6), or 5 microM paracetamol with a 50:50 molar mixture of genistein and biochanin A or daidzein and formononetin, at a total isoflavone concentration of 1 and 10 microM (n = 6 for each mixture at each concentration). At 1 microM, neither isoflavone mixture had any effect, while at 10 microM both mixtures decreased the clearance of paracetamol and the formation clearance to paracetamol sulfate. Genistein and biochanin A (10 microM) also increased the biliary extraction of hepatically-generated paracetamol sulfate. Additional livers were perfused with an infusion of 5 microM (14)C-paracetamol in the absence (n = 4), or presence, of a 10 microM genistein and biochanin A mixture (n = 4). Analysis of washout perfusate and bile samples (up to 30 min after stopping the infusion) revealed that the isoflavones reduced the first-order rate constant for paracetamol sulfate transport into perfusate, but not for transport into bile. The results indicate that isoflavones can reduce the formation of paracetamol sulfate and that its enhanced excretion into bile arises from the inhibition of sinusoidal efflux transport.