Organic acid transport

About: Organic acid transport is a research topic. Over the lifetime, 169 publications have been published within this topic receiving 293189 citations.

Renal tubular transport: accumulation of p-aminohippurate by rabbit kidney slices.

Abstract: I NVESTIGATIONS on the biochemical mechanisms involved in active renal tubular transport are difficult to approach with the various experimental techniques now available. The study of isolated enzyme systems can at best present only a fragmentary picture of a complex physiological process. The clearance technique, while permitting precise measurement of certain tubular activities throws little light on the nature of the underlying chemical events and, in addition, is handicapped by certain limitations inherent in intact animal experimentation. Consequently, there is a need for simple experimental procedures which will permit a>, the observation of events which accurately reflect tubular transport, b) the simultaneous measurement of certain metabolic activities, and c) the variation of experimental conditions over a broader range than can be achieved in the intact animals. The present paper is concerned with the development of such a technique and with preliminary observations on the cellular transport of p-aminohippurate (PAH). The procedure described in this paper is an outgrowth of several previously employed. Chambers and his associates (I) have observed microscopically the transport of phenol red into the tissue-cultured cysts of embryo chick mesonephros and have reported on the effects of several metabolic inhibitors on this process. Forster (2) has since devised a somewhat simpler procedure utilizing the thin kidney slices or isolated renal tubules of various cold blooded animals. The first paper of this series (3) dealt with observations obtained with this technique. Unfortunately, such studies depend upon the frequent, direct visualization of the kidney tissue and are necessarily limited to colored compounds. More recently, Stern et al. (4) have shown that brain slices, incubated in a saline medium in the Warburg apparatus, are capable of accumulating glutamate against a considerable concentration gradient. We have found that this technique can be readily adapted to the study of certain renal transport mechanisms.

Influence of increased membrane cholesterol on membrane fluidity and cell function in human red blood cells

Abstract: Cholesterol and phospholipid are the two major lipids of the red cell membrane. Cholesterol is insoluble in water but is solubilized by phospholipids both in membranes and in plasma lipoproteins. Morever, cholesterol exchanges between membranes and lipoproteins. An equilibrium partition is established based on the amount of cholesterol relative to phospholipid (C/PL) in these two compartments. Increases in the C/PL of red cell membranes have been studied under three conditions: First, spontaneous increases in vivo have been observed in the spur red cells of patients with severe liver disease; second, similar red cell changes in vivo have been induced by the administration of cholesterol-enriched diets to rodents and dogs; third, increases in membrane cholesterol have been induced in vitro by enriching the C/PL of the lipoprotein environment with cholesterol-phospholipid dispersions (liposomes) having a C/PL of greater than 1.0. In each case, there is a close relationship between the C/PL of the plasma environment and the C/PL of the red cell membrane. In vivo, the C/PL mole ratio of red cell membranes ranges from a normal value of 0.09--1.0 to values which approach but do not reach 2.0. In vitro, this ratio approaches 3.0. Cholesterol enrichment of red cell membranes directly influences membrane lipid fluidity, as assessed by the rotational diffusion of hydrophobic fluorescent probes such as diphenyl hexatriene (DPH). A close correlation exists between increases in red cell membrane C/PL and decreases in membrane fluidity over the range of membrane C/PL from 1.0 to 2.0; however, little further change in fluidity occurs when membrane C/PL is increased to 2.0--3.0. Cholesterol enrichment of red cell membranes is associated with the transformation of cell contour to one which is redundant and folded, and this is associated with a decrease in red cell filterability in vitro. Circulation in vivo in the presence of the spleen further modifies cell shape to a spiny, irregular (spur) form, and the survival of cholesterol-rich red cells is decreased in the presence of the spleen. Although active Na-K transport is not influenced by cholesterol enrichment of human red cells, several carrier-mediated transport pathways are inhibited. We have demonstrated this effect for the cotransport of Na + K and similar results have been obtained by others in studies of organic acid transport and the transport of small neutral molecules such as erythritol and glycerol. Thus, red cell membrane C/PL is sensitive to the C/PL of the plasma environment. Increasing membrane C/PL causes a decrease in membrane fluidity, and these changes are associated with a reduction in membrane permeability, a distortion of cell contour and filterability and a shortening of the survival of red cells in vivo.

Pharmacokinetics in older persons.

Abstract: Background: Physiologic changes and disease-related alterations in organ function occur with aging. These changes can affect drug pharmacokinetics in older persons. Objective: This article reviews age-related changes in pharmacokinetics and their clinical relevance. Methods: A PubMed search was conducted using the terms elderly and pharmacokinetics . Other reviews were also included for literature searching. The review includes literature in particular from 1990 through April 2004. Some particles from before 1990 were included to help illustrate principles of age-related pharmacokinetics. Results: There are minor changes in drug absorption with aging. The effect of aging on small-bowel transporter systems is not yet fully established. Bioavailability of highly extracted drugs often is increased with age. Transdermal absorption may be delayed, especially in the case of water-soluble compounds. Fat-soluble drugs may distribute more widely and water-soluble drugs less extensively in older persons. Hepatic drug metabolism shows wide interindividual variation, and in many cases, there is an age-related decline in elimination of metabolized drugs, particularly eliminated by the cytochrome enzyme system. Any decrement in cytochrome enzyme metabolism appears nonselective. Synthetic conjugation metabolism is less affected by age. Pseudocapillarization of the sinusoidal endothelium in the liver, restricting oxygen diffusion, and the decline in liver size and liver blood flow may influence age-related changes in rate of hepatic metabolism. Frailty, physiological stress, and illness are important predictors of drug metabolism in older individuals. Inhibition of drug metabolism is not altered with aging, but induction is reduced in a minority of studies. Renal drug elimination typically declines with age, commensurate with the fall in creatinine clearance. Renal tubular organic acid transport may decline with age, while the function of the organic base transporter is preserved but may be less responsive to stimulation. Conclusion: Changes in pharmacokinetics occur due to age-related physiologic perturbations. These changes contribute to altered dose requirements in older persons, particularly in the case of drugs eliminated by the kidney. Interindividual variation, disease, frailty, and stress may overshadow age-related changes.

Clinical pharmacokinetics of methotrexate

Abstract: The absorption of methotrexate following intramuscular injection and oral administration of small doses (>30mg/m2) is rapid and complete, whereas with oral doses in excess of 80mg/m2 absorption is less than complete. Pretreatment with oral neomycin decreases and with kanamycin increases the gastrointestinal absorption of oral methotrexate. The plasma disposition of methotrexate is multiexponential. Due to differences in sampling schedule and assay methods, widely varying estimates of elimination half-life (tJ/2β of 6 to 69 hours of methotrexate have been reported. The long half-life may either be due to enterohepatic circulation of methotrexate and/or its metabolites or a slow elimination of dihydrofolate reductase (DHFR) bound methotrexate. The plasma clearance of methotrexate following small clinical doses is about 80ml/min, but may become saturated at high doses (20g). During high dose infusions, the peak plasma level is proportional to doses up to 200mg/kg. Methotrexate is transported across cellular membranes via a carrier-mediated active type process. At high concentrations, when the carrier route is saturated, passive diffusion assumes greater importance. Methotrexate is not highly bound to plasma proteins (∼50%). However, being highly ionised at physiological pH, the drug does not accumulate in the cerebrospinal fluid to any appreciable extent, necessitating intrathecal administration in the treatment of cerebral and meningeal metastases. Renal excretion is the major route of elimination for methotrexate (∼80% ); the drug being actively secreted in the renal tubule by the general organic acid transport system. Hence, the renal clearance of methotrexate is decreased by the concomitant administration of organic acids, such as salicylate. The renal clearance of methotrexate is correlated with endogenous creatinine clearance which may provide a guideline to dosage adjustments according to renal function and age. With high dose methotrexate, routine administration of fluid and/or bicarbonate is recommended to prevent intratubular precipitation of the drug. Biliary excretion of methotrexate constitutes less than 10% of the administered dose. Other extrarenal routes of excretion such as secretion into human breast milk and saliva are negligible. About a third of an oral dose of methotrexate is metabolised by intestinal bacteria during absorption. The major metabolite is 4-amino-4-deoxy-N10-methylpteroic acid. Small amounts (<11%) of 7 -hydroxymethotrexate have also been found in urine of patients receiving high dose methotrexate therapy. Except for the poly-γ-glutamates, all of the reported metabolites are less effective than methotrexate as an inhibitor of dihydrofolate reductase. As determined by inhibition of DNA synthesis, normal tissues are sensitive to low levels of methotrexate (∼10−8M) Furthermore, toxicity with methotrexate is related to duration of exposure as well as to the dose or plasma concentration. Impurities, such as methopterin and other byproducts of the synthetic process have been found in commercial parenteral dosage forms of methotrexate. The clinical significance of these impurities requires further study. For a phase-specific chemotherapeutic agent such as methotrexate, effective plasma levels of the drug should be maintained during the proliferative phase of the tumour cell cycle to achieve a maximum cytotoxic effect. Monitoring the plasma level of methotrexate, particularly during high dose therapy, may provide information regarding impending toxicity and the need for extended citrovorum factor rescue.