Erythrocytes lithium

Okpaku, S., Frazer, A. Mendels, J. (2005). A pilot study of racial differences in erythrocyte lithium transport. Am.. Psychiatry, 137, 120-1. 

In a comparison of lithium concentrations in erythrocytes and plasma during acute or chronic lithium intoxication (309 samples in 165 patients) good general correlation between erythrocyte and plasma lithium concentrations was confirmed (735). There were higher plasma lithium concentrations in acute intoxication and higher erythrocyte lithium concentrations in chronic intoxication the lithium erythrocyterplasma concentration ratio was highest in those with chronic intoxication. 

There may be abnormalities in eiythrocyte membrane transport properties in patients with bipolar affective disorders, though the interpretation is confounded by the uncertainty with regard to the contribution of hypertension in patients who are coincidentally hypertensive and manic depressive. The administration of lithium also may cause adaptive change (93,117,135-137). This results in an increase in erythrocyte lithium concentrations after prolonged lithium therapy, which could be mediated either by increased flux into the cell or via reduction in efflux rate. An increased content of ankyrins, red cell membrane proteins affecting cytoskeletal structure and functions, has been found in some patients with bipolar affective disorder (138) and this raises further the role of erythrocyte membrane defects in the etiology of the disease. 

Measuring erythrocyte lithium concentrations does not appear to offer any advantages over serum lithium determinations in the management of lithium toxicity [94 ]. 

Mendlewicz, J., Verbanck, P., Linkowski, P. Wilmotte, J. (1978). Lithium accumulation in erythrocytes of manic-depressive patients an in vivo twin study. Br. J. Psychiatry, 133,436-44. 

Most human cells are exposed to less than 2 mM Li+, and in most tissues the intracellular Li+ concentration is lower than the extracellular concentration. The level inside cells is generally below that expected for the passive diffusion of the Li+ ion across the cell membrane, indicating that Li+ is actively transported out of cells. For instance, the concentration of Li+ inside the erythrocytes from people taking lithium salts is low with a typical ratio of intra- to extracellular Li+ of 0.5 [53]. 

Abnormalities in the movement of Li+ across the erythrocyte membrane have been related to psychiatric disorders and also in response to lithium therapy itself. As yet there is relatively little definitive information about the Li+ transport mechanisms operating in therapeutically relevant cell types. 

In contrast to the limited value of pharmacokinetics to the use of antidepressants, knowledge of the kinetics of lithium has been important in defining the therapeutic and toxic range in unipolar or bipolar manic patients. Prediction of the dose required by the individual patient by giving a single dose of the drug and measuring the erythrocyte/plasma lithium... 

Ehrensing RH, Kastin AJ Dose-related biphasic effect of prolyl-leucylglycinamide (MlF-1) in depression. Am J Psychiatry 135 562-566, 1978 Ehrlich BE, Diamond JM, Ery V, et al Lithium s inhibition of erythrocyte cation countertransport involves a slow process in the erythrocyte. J Membr Biol 75 233-240, 1983... 

Hokin-Neaverson M, Jefferson JW Deficient erythrocyte Na,K-ATPase activity in different affective states in bipolar affective states in bipolar affective disorder and normalization by lithium therapy. Neuropsychobiology 22 18-25, 1989a Hokin-Neaverson M, Jefferson JW Erythrocyte sodium pump activity in bipolar affective disorder and other psychiatric disorders. Neuropsychobiology 22 1-7, 1989b... 

Hokin-Neaverson M, Burckhardt WA, Jefferson JW Increased erythrocyte Na" pump and Na-K-ATPase activity during lithium therapy. Research Communications in Chemical Pathology and Pharmacology 14 117-126, 1976 Holazo AA, Winkler MB, Patel IH Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol 28 1040-1045, 1988... 

Jope RS, Jenden DJ, Ehrlich BE, et al Choline accumulates in erythrocytes during lithium therapy. N Engl J Med 299 833-834, 1978 Jope RS, Jenden DJ, Ehrlich BE, et al Erythrocyte choline concentrations are elevated in manic patients. Proc Natl Acad Sci USA 77 6144-6146, 1980 Jope RS, Morrisett RA, Snead OC Characterization of lithium potentiation of pilocarpine induced status epilepticus in rats. Exp Neurol 91 471-480, 1986 Jordan D, Spyer KM Brainstem integration of cardiovascular and pulmonary afferent activity. Prog Brain Res 67 295-314, 1986... 

Lee G, lingsch C, Lyle PT, et al Lithium treatment strongly inhibits choline transport in human erythrocytes. Br J Chn Pharmacol 1 365-370, 1974 Lee KF, li E, Huber J, et al Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral nervous system. Cell 69 737-749, 1992... 

Nasrallah HA, Varney N, Coffman JA, et al Opiate antagonism fails to reverse post-ECT cognitive deficits. J Clin Psychiatry 47 555-556, 1986 Nasrallah HA, Coffman JA, Olson SC Structural brain-imaging findings in affective disorders an overview. J Neuropsychiatry Clin Neurosci 1 21-26, 1989 Naylor GJ, Smith AHW Defective genetic control of sodium-pump density in manic depressive psychosis. Psychol Med 11 257-263, 1981 Naylor GJ, McNamee HB, Moody JP Erythrocyte sodium and potassium in depressive illness. J Psychosom Res 14 173-177, 1970 Naylor GJ, McNamee HB, Moody JP Changes in erythrocyte sodium and potassium on recovery from depressive illness. Br J Psychiatry 118 219-223, 1971 Naylor GJ, Dick DAT, Dick EG, et al Lithium therapy and erythrocyte membrane cation carrier. Psychopharmacologia 37 81-86, 1974 Naylor GJ, Smith AHW, Dick EG, et al Erythrocyte membrane cation carrier in manic-depressive psychosis. Psychol Med 10 521-525, 1980... 

Ryan ND, Dahl RE The biology of depression in children and adolescents, in Biology of Depressive Disorders, Part B Subtypes of Depression and Gomorbid Disorders. Edited by Mann JJ, Kupfer D. New York, Plenum, 1994 Rybakowski J, Erazer A, Mendels J Lithium efflux from erythrocytes incubated in vitro during lithium carbonate administration. Communications in Psychopharmacology 2 105-112, 1978... 

Uney JB, Marchbanks RM, Marsh A The effect of lithium on choline transport in human erythrocytes. J Neurol Neurosurg Psychiatry 48 229-233, 1985... 

The effects of lithium on hemopoiesis have been studied in 100 patients who had developed chronic granulocytopenia after cancer chemotherapy or radiotherapy (240). The mean leukocyte count rose by 46%, but there were no changes in platelet or erythrocyte counts. However, there was a significant increase in platelet count in those whose baseline values were below 150 x 109/1. Lithium was well tolerated (mean serum concentration 0.59 mmol/1). 

A cross-sectional study showed a 20% lower serum vitamin B12 concentration in patients taking lithium (n = 81) than in controls (n = 14) (serum and erythrocyte folate concentrations were normal) (346). 

Erythrocyte/plasma lithium concentration ratios were lower in patients taking phenothiazines or haloperidol than in those taking lithium alone (620,621), and the former group had a higher incidence of neurological and renal adverse effects (621). 

In a pharmacokinetic study in healthy volunteers ketorolac increased the concentration of lithium in both serum and erythrocytes, which may reflect concentration of the drug in the nervous system more accurately. Ketorolac can therefore increase the risk of adverse reactions of lithium (683), as do many other NSAIDs. 

Biochemical variables in erythrocytes, mood states, and adverse effects of lithium were measured in 30 patients, mostly men, who had bipolar disorder and were undergoing lithium treatment (736). Most (87%) had bipolar I affective disorder. The major finding was that when the serum lithium concentration was in the 0.93-1.42 mmol/1 range, there was a full response without toxicity. Higher values predicted toxicity and lower values predicted partial response. 

Distribution in Blood. Lithium is taken up by erythrocytes to a variable extent which appears to be partly genetically determined. 

Erythrocyte/plasma lithium concentration ratios were lower in patients taking phenothiazines or haloperidol... 

It has been claimed by some workers that Li is more readily transported into erythrocytes than is Li and that there are differences in their biological effects (72). It has also been postulated that Li may produce fewer side effects or less toxicity than the naturally occurring isotope mixture (73). Li nuclear magnetic resonance (NMR) spectroscopy in vivo has been used to measure tissue lithium levels in humans noninvasively and with safety. These experiments showed tissue lithium concentrations significantly lower than those in the serum (74). The NMR technique has been used also to distinguish the isotopes in transport studies in red blood cells (75, 76) and in other cell types (77). 

The most extensive studies for lithium transport across cell membranes have used erythrocytes because they are readily obtained and occur as individual cells freely floating in a suspending plasma medium. However, lithium uptake in these cells may not reflect uptake into other tissues due to their atypical morphology and metabolism. 

Lithium uptake experiments in erythrocytes may have value in the prediction of those patients who are most likely to respond to treatment (114-117). Other studies have used squid axon, hepatocytes, 3T3 fibroblast cell cultures, and liposomes to investigate lithium transport across the plasma membrane (77, 118). 

Five pathways for lithium transport in erythrocytes have been described (119) ... 

Efflux of lithium occurs via sodium-lithium countertransport. It is ouabain insensitive, blocked by phloretin, independent of ATP, and exhibits saturation. A 1 1 stoichiometry occurs and the maximum affinity for both cations occurs at the internal surface, that for lithium being 20-30 times higher than for sodium (120). Chronic administration of lithium in humans eventually reduces lithium-sodium countertransport in erythrocytes (121). 

Sodium-lithium countertransport, anion exchange, and the leak mechanism are the most important transport routes for lithium in vivo. Lithium appears to substitute for sodium in all of these pathways in the erythrocytes (131) and also in the squid axon membrane (132). Sodium-lithium countertransport has been claimed to be abnormal in patients suffering from essential hypertension and in their close relatives (133). However, despite a decade of experimental study by many different laboratories, there is no consensus with regard to the true basis of the membrane defect, if indeed it is really present. Nor is it clear under what precise conditions the abnormality is manifest (134). 

Lithium efflux from human erythrocytes ultimately becomes inhibited by approximately 50% in people whose plasma contains lithium at... 

Genetically determined variations in the distribution of lithium between plasma and erythrocytes have been found in sheep (Schless et. al. 1975). Likewise, depressive patients react differently to lithium treatment, with heredity a probable contributory factor, as has been shown investigations conducted in twins. A hereditary recessive primary hypomagnesemia that is accompanied by a low level of calcium in the blood leads to tetany. This is presumably caused by a nonfunctional magnesium resorption in the intestine (Lombeck and Bremer... 

ScHLESs AP, Frazer A, Mendels J, Panday GN and Theodorides VJ (1975) Genetic determination of lithium ion metabolism. 11. An in vivo study of lithium ion distribution across erythrocyte membranes. Arch Gen Psychiatry 32 337-340. 

Numerous investigations on the transport of the lithium ion through cell membranes of erythrocytes have established five different pathways by which anion exchange and sodium-potassium co-transport control lithium uptake into the cell, whilst... 

---