The mechanism of action of clofibrate and tetranicotinoylfructose (Bradilan) on the kinetics of plasma free fatty acid and triglyceride transport in type IV and type V hypertriglyceridaemia

Abstract. The kinetics of plasma free fatty acid and triglyceride transport were assessed in 20 patients with idiopathic hypertriglyceridaemia. These patients were subdivided according to lipoprotein pattern into Type IV and Type V patients. The effects of clofibrate therapy on plasma free fatty acid and triglyceride kinetics were assessed in these patients. Clofibrate produced a marked reduction in serum triglyceride associated with a significant reduction in triglyceride turnover as well as enhancement of triglyceride clearance. The reduction in triglyceride concentration produced by clofibrate was found to correlate with the reduction in free fatty acid turnover indicating that this drug decreased the availability of free fatty acid turnover indicating that this drug decreased the availability of free fatty acids for hepatic esterification. Clearance of endogenous plasma triglyceride was markedly enhanced in those patients in whom it was markedly impaired before treatment.—Having discontinued clofibrate for six weeks the same patients received bradilan (tetranicotinoylfructose) and kinetic measurements were repeated. It was evident that bradilan had a greater hypotriglyceridaemic effect than clofibrate in both groups of patients. The effect of bradilan was the result of inhibition of free fatty acid turnover and consequently a marked reduction in triglyceride turnover. Bradilan, unlike clofibrate, did not affect the mechanisms responsible for the clearance of plasma triglycerides.     

The Kinetics of Plasma Free Fatty Acid and Triglyceride Transport in Patients with Idiopathic Hypertriglyceridaemia and Their Relation to Carbohydrate Metabolism

Abstract. Plasma free fatty acid and triglyceride transport kinetics were assessed in 20 patients with idiopathic hypertriglyceridaemia. None of these patients had abnormal glucose tolerance. They included 10 patients in whom the serum triglyceride elevation was due to an increase in the circulating VLDL (Fredrickson Type IV) and 10 in whom the increase in plasma VLDL was associated with hyperchylomicronaemia (Fredrickson Type V). These were compared with a control group of 27 normal subjects.–Increased plasma triglyceride turnover with normal clearance was observed in the Type IV patients suggesting that the hypertriglyceridaemia in these patients was predominantly due to enhancement of plasma triglyceride production. The plasma triglyceride concentration correlated closely with the changes in triglyceride turnover rate.–Studies performed in the Type V patients showed an increase in the plasma triglyceride turnover rate in only 3 subjects, while in the remaining patients the turnover values were similar to those of the control subjects. The increase in serum triglyceride concentration found in some of the patients was due to an increase in plasma triglyceride production. However, in the majority of patients in this group impairment of plasma triglyceride clearance was the predominant abnormality.–In both hypertriglyceridaemic groups the plasma FFA flux was markedly increased and correlated significantly with the degree of hypertriglyceridaemia. The increase in triglyceride turnover observed in Type IV patients and some of the Type V patients correlated closely with the enhancement of plasma FFA flux suggesting that the increase in triglyceride production in these patients was secondary to enhanced lipolysis.–The plasma insulin response to an oral glucose load was markedly increased in both groups of hypertriglyceridaemic patients and correlated significantly with the elevation in serum triglyceride concentration. The plasma insulin response also correlated with the plasma free fatty acid turnover.–The results suggest that the initial lesion in these patients was related to insulin unresponsiveness in adipose tissue resulting in enhanced lipolysis with secondary changes in insulin secretion and plasma triglyceride transport kinetics.     

The kinetics of plasma free fatty acid and triglyceride transport in patients with idiopathic hypertriglyceridaemia and their relation to carbohydrate metabolism

Abstract. Plasma free fatty acid and triglyceride transport kinetics were assessed in 20 patients with idiopathic hypertriglyceridaemia. None of these patients had abnormal glucose tolerance. They included 10 patients in whom the serum triglyceride elevation was due to an increase in the circulating VLDL (Fredrickson Type IV) and 10 in whom the increase in plasma VLDL was associated with hyperchylomicronaemia (Fredrickson Type V). These were compared with a control group of 27 normal subjects.—Increased plasma triglyceride turnover with normal clearance was observed in the Type IV patients suggesting that the hypertriglyceridaemia in these patients was predominantly due to enhancement of plasma triglyceride production. The plasma triglyceride concentration correlated closely with the changes in triglyceride turnover rate.—Studies performed in the Type V patients showed an increase in the plasma triglyceride turnover rate in only 3 subjects, while in the remaining patients the turnover values were similar to those of the control subjects. The increase in serum triglyceride concentration found in some of the patients was due to an increase in plasma triglyceride production. However, in the majority of patients in this group impairment of plasma triglyceride clearance was the predominant abnormality.—In both hypertriglyceridaemic groups the plasma FFA flux was markedly increased and correlated significantly with the degree of hypertriglyceridaemia. The increase in triglyceride turnover observed in Type IV patients and some of the Type V patients correlated closely with the enhancement of plasma FFA flux suggesting that the increase in triglyceride production in these patients was secondary to enhanced lipolysis.—The plasma insulin response to an oral glucose load was markedly increased in both groups of hypertriglyceridaemic patients and correlated significantly with the elevation in serum triglyceride concentration. The plasma insulin response also correlated with the plasma free fatty acid turnover.—The results suggest that the initial lesion in these patients was related to insulin unresponsiveness in adipose tissue resulting in enhanced lipolysis with secondary changes in insulin secretion and plasma triglyceride transport kinetics.     

Plasma Endogenous Triglyceride Transport in Hypertriglyceridaemia and Effect of a Hypolipidaemic Drug (SU-13437)

Abstract. The kinetics of plasma endogenous triglyceride transport were assessed in nine hyperglyceridaemic patients before and after treatment with an effective hypolipidaemic compound of the clofibrate group, phenolic ether Su-13437. The triglyceride turnover was measured by endogenous ³H-glycerol labelling technique and the results were compared to those obtained earlier in selected normal subjects. In the untreated stage the plasma triglyceride transport (production) rate was above the normal range in seven of the nine patients but it did not correlate with the triglyceride concentration. On the other hand, the logarithm of the concentration showed a significant inverse correlation with the fractional transport rate. During administration of the drug both the plasma triglyceride concentration and production rate fell in all subjects, the mean decreases being 52 and 35%, respectively. The response of the fractional transport rate to treatment was very variable and although the mean increase of 26% was significant the change did not correspond to the decrease in the triglyceride concentration. On the basis of these observations it is suggested that the primary defect in most cases of type IV endogenous hyperglyceridaemia is an increased inflow transport of plasma triglycerides but the actual plasma triglyceride level is ultimately determined by the inherent type of transport kinetics. The compound Su-13437 is an effective triglyceride-concentration-lowering agent which acts mainly by decreasing the production of plasma triglycerides.     

Plasma Triglyceride and Fatty Acid Metabolism in Diabetes mellitus

Abstract. Free fatty acid and triglyceride metabolism was studied in diet-responsive and insulin-dependent diabetics and in non-diabetic obese patients before and during treatment. Free fatty acid turnover was elevated in diabetics and in most obese patients, and was decreased by diabetic control; it showed no significant change in the obese patients during caloric restriction. Plasma triglyceride levels exceeded 160 mg/100 ml in 20 of the 34 diabetics, and gross lipaemia occurred both in insulin-requiring and diet-responsive patients. The fractional turnover of injected triglyceride was low in 20 of 33 measurements on untreated diabetics, and was negatively correlated with endogenous triglyceride levels. The fractional turnover increased significantly during diabetic control. These findings are compatible with the view that diabetic hypertrigly ceridaemia may be due in part to impaired removal of triglyceride from plasma.     

Influence of chenodeoxycholic acid on the kinetics of endogenous triglyceride transport in man.

Plasma lipids and triglycerides kinetics were studied in ten subjects before and after 6-8 weeks treatment with 1 g/day chenodeoxycholic acid for radiolucent gallstones. Plasma triglyceride concentration fell by 20% and phospholipid concentration rose by 5% on average; there was no change in cholesterol or free fatty acids. Body weight remained constant. Triglyceride kinetics, studied by a precursor-labelling technique, revealed a reduction both of triglyceride plasma pool and turnover rate, accompanied by a decline of more than 35% both of plasma triglyceride precursor pool and of incorporation of plasma free fatty acids into newly synthesized plasma triglycerides. Fractional turnover rates in both pools remained unaltered. The appearance-time for newly synthesized plasma triglycerides after injection of label did not change. These results indicate that chenodeoxycholic acid lowers plasma triglyceride by reducing its synthesis, thereby precluding alternative, and possibly undesired, modes of action, such as impaired secretion or increased peripheral catabolism of endogenous triglyceride. Several biochemical mechanisms may be responsible for this effect, among which stimulation of phospholipid synthesis by bile acids could play a role.     

Mechanism of the Hypolipemic Effect of Clofibrate in Postabsorptive Man

Splanchnic metabolism of triglycerides and other major substrates was studied in the postabsorptive state in normotriglyceridemic and hypertriglyceridemic human subjects who received (1/2) g of clofibrate four times daily for 3 wk. Transport in blood plasma of triglycerides produced in the splanchnic region was quantified by three methods: (a) measurement of the transsplanchnic gradient of (14)C-labeled triglycerides during constant intravenous infusion of [1- (14)C] palmitate (b) chemical measurement of the transplanchnic gradient in concentration of triglycerides of very low density lipoproteins; and (c) determination of clearance of (14)C-labeled triglycerides in extrasplanchnic tissues. The first method measures only triglycerides derived from free fatty acids and the last two measure total splanchnic production. In hypertriglyceridemic subjects treated with clofibrate, average rates of total splanchnic production of triglycerides and production from free fatty acids were the same as those of comparable untreated subjects despite a consistent fall in plasma triglyceride levels. The hypotriglyceridemic effect of the drug was therefore accompanied by improved disposal of triglycerides in extrasplanchnic tissues. In treated normotriglyceridemic subjects, unlike their untreated counterparts, total splanchnic production was significantly higher than production from free fatty acids. Failure of clofibrate to reduce triglyceride levels in normotriglyceridemic subjects may have been related to increased total splanchnic production, coupled with improved extrasplanchnic disposal.Systemic transport and net splanchnic uptake of free fatty acids were similar in treated and control subjects but the fraction of [1-(14)C]palmitate converted to acetoacetate in splanchnic tissues was significantly higher in treated subjects. Net splanchnic extraction of plasma amino acids that enter the glucogenic pathway via pyruvate was increased in treated subjects and their arterial concentrations were reduced.     

The role of dietary lipid in the regulation of unconjugated hyperbilirubinaemia in Gunn rats

1. The purpose of this study was to characterize the mechanisms of diet-induced hyperbilirubinaemia in Gunn rats with emphasis on the role of lipids, and to examine their relationship with regard to fasting hyperbilirubinaemia. 2. A lipid-free normocaloric diet produced a threefold increase in plasma bilirubin concentration (baseline 109.4 mumol/l), which was maximal by 10 days and thereafter remained constant. The level of hyperbilirubinaemia attained was not influenced by fasting or phenobarbitone, and returned to baseline concentration within 10 days of resuming a normal diet. 3. Determination of hepatic bilirubin showed that the magnitude of the hepatic bilirubin pool was increased by the lipid-free diet but was unchanged by fasting. Hepatic ligandin concentrations were comparable in fasted Gunn rats and those fed normal or lipid-free diets, although total hepatic ligandin was reduced in the fasted animals. 4. The hyperbilirubinaemic effect of the lipid-free diet was largely reversed by the inclusion of 10% lipid in the diet and was affected to a lesser extent by 5% lipid. Similar reductions in plasma bilirubin concentration were observed with a variety of other lipids (10%), regardless of their fatty acid chain length or degree of saturation. 5. In fasting animals a direct correlation was observed between plasma bilirubin and free fatty acid concentrations and insulin levels were greatly depressed, whereas in those fed on the lipid-free diet no significant changes were evident in plasma concentrations of free fatty acids or insulin. 6. Plasma bilirubin concentration was unrelated to alterations in plasma triglycerides produced by the administration of clofibrate. However, an unexplained decrease in plasma bilirubin (40%) without a significant change in triglycerides was noted when clofibrate was added to the lipid-free diet. 7. Analysis of kinetic data obtained from [14C]bilirubin clearance studies revealed that hyperbilirubinaemia associated with the lipid-free diet reflected a marked reduction (60%) in plasma clearance with no change in bilirubin turnover. This was accompanied by a relative redistribution of bilirubin from the extravascular pool to the plasma pool. 8. Although these studies indicate that fasting and the withdrawal of dietary lipid have some similar effects on bilirubin metabolism, it seems likely that different mechanisms are responsible for the hyperbilirubinaemia.     

The Effects of Colestipol Resin and of Colestipol Plus Clofibrate on the Turnover of Plasma Cholesterol in Man

Studies were conducted to determine the effects of colestipol hydrochloride, a new bile acid-sequestrant resin, on some of the parameters of cholesterol turnover and metabolism in man. Three normal volunteers and eight hyperlipidemic patients participated in three sets of cholesterol turnover studies carried out at intervals of approximately 1 yr. The effects of colestipol were assessed by comparing the results obtained before therapy with those obtained on repeat study after several months of resin therapy. Colestipol treatment significantly reduced the serum cholesterol concentration (mean reduction 21%), and produced a large increase in the production rate of cholesterol (mean 86%) and in the turnover rate of cholesterol in pool 1 (mean 46%). The values of the intercompartmental rate constants and of the size of the rapidly exchangeable pool were unchanged with therapy.The turnover studies were carried out for 12-13 wk, and were analyzed according to a two-pool model. Although long-term studies of cholesterol turnover conform to a three-pool, rather than a two-pool model, the present studies probably provide a valid estimate of the effects of therapy on certain parameters, namely the production rate, the size, and the turnover rate of pool 1.Repeated studies in four untreated subjects showed a striking constancy with time for the kinetic parameters for each subject. The production rate was particularly constant from year to year for a given subject, and showed a pooled standard deviation of only 3%. The findings suggest that the total body turnover of cholesterol is under close homeostatic control in an integrated manner.Combined drug therapy with colestipol plus clofibrate further reduced the serum cholesterol level in three of four patients, and reduced the triglyceride level in all four patients. Addition of clofibrate to the treatment program produced only small decreases in the production rate, which were not significantly different from the small decreases seen in two patients who were continued (and restudied) on colestipol alone. The findings do not support the suggestion that clofibrate can block the increased rate of cholesterol synthesis and turnover resulting from bile acid-sequestrant treatment. The effects on serum lipids, however, make the combined drug therapy potentially quite useful.     

Plasma Triglyceride Metabolism in the Adult Nephrotic Syndrome

Abstract. The kinetic parameters of plasma triglyceride metabolism were determined in 14 adult subjects with the nephrotic syndrome by endogenous labelling of circulating triglyceride with tritiated glycerol. The triglyceride production (turnover) rate and the apparent K_m of removal were calculated from the slope of the radioactivity disappearance curve and compared to a normal control material studied previously. Plotting of the individual data in a log scale of triglyceride concentration versus turnover with the normal area and saturation curves in the background allowed a detailed characterization of the nature of kinetic alterations occurring in disease. It was found that in the majority of cases with the nephrotic syndrome the plasma triglyceride concentration and rate of influx are slightly above normal. However, the apparent K_m of removal was significantly increased suggesting that efflux may also be somewhat impaired. In four cases the plasma triglyceride was produced at a rate which exceeded the value predicted by the normal saturation curves and it is believed that an uncontrolled overproduction of plasma triglyceride was present in these cases.—Complete remission of disease in one case brought both triglyceride concentration and turnover rate rapidly to normal values. An eight-hour infusion of human serum albumin in another patient promptly caused a return of high triglyceride turnover to normal.— The primary change behind the nephrotic hypertriglyceridaemia seems to be a controlled increase of plasma triglyceride synthesis. In some cases, however, this overproduction occurs in an uncontrolled fashion and in a number of patients decrease of removal efficiency contributes to the development of hyperglyceridaemia. All of these changes can be explained on the basis of an increased FFA/albumin molar ratio in plasma giving rise to the elevation of unbound FFA fraction.     

Metabolism of Very Low Density Lipoproteins in Hyperlipidaemia: Studies of Apolipoprotein B Kinetics in Man

The metabolism of very low density lipoprotein-B (VLDL-B) peptide was studied in nineteen subjects with endogenous hypertrigylceridaemia (Types V, IV and lib), three patients with heterozygous familial hyperbetalipoproteinaemia (Type Ila) and eight healthy subjects, by reinjecting autologous radioiodinated VLDL. The kinetics of VLDL-B peptide were followed. The mean turnover rate of VLDL-B peptide was significantly higher in the hypertriglyceridaemic group than in the control group but a considerable overlap in turnover rate was found between these groups. The patients with heterozygous familial hyperbetalipoproteinaemia had a normal turnover rate of VLDL-B peptide. A significant positive correlation was found between the turnover rate of VLDL-B peptide and VLDL-triglyceride concentration in the whole series. It is concluded that the underlying defect in endogenous hypertriglyceridaemia is heterogeneous. Overproduction of VLDL is a major determining factor in seme patients whereas a reduced clearance is the determining factor in others.     

Splanchnic Secretion Rates of Plasma Triglycerides and Total and Splanchnic Turnover of Plasma Free Fatty Acids in Men with Normo- and Hypertriglyceridaemia

Abstract. Plasma triglyceride (TG) “turnover rates” were estimated in the fasting state in three different ways: splanchnic chemical TG secretion, splanchnic isotope TG secretion and plasma TG clearance. Forty-two men with a wide range of fasting plasma TG concentrations, from 0.53 to 16.50 mmol/l were investigated. A constant intravenous infusion of albumin-bound ³H-labelled palmitate was given and blood was simultaneously sampled from the hepatic vein and an artery for determination of hepatic venous-arterial differences of labelled and unlabelled plasma TG. In addition total and splanchnic turnovers of plasma FFA were measured. Similar values were obtained for plasma TG “turnover rate” by the splanchnic chemical TG secretion and the plasma TG clearance method. The values for these two methods varied between 3 and 74 μmol/min. and m² body surface area, except for two cases who had considerably higher values. The splanchnic isotope TG secretion method gave lower values varying from 1 to 34 μmol/min. and m² body surface area. This method probably measures only that fraction of the splanchnic TG secretion which is derived from plasma FFA. No correlations were found among normotriglyceridaemic subjects between plasma total TG or VLDL-TG concentrations and plasma TG “turnover rates” measured by any of the three methods. For patients with hypertriglyceridaemia significant positive correlations were found between plasma VLDL-TG concentrations and plasma “turnover rates”. The “fractional turnover rate” decreased with increasing TG levels in an apparently hyperbolic fashion. The results suggest an impaired plasma TG removal capacity in patients with hypertriglyceridaemia. In 7 out of 14 patients the plasma TG “turnover rates” were in the upper part of the normal range and seemed to have contributed to the hypertriglyceridaemia in these patients. Plasma FFA turnover rate ranged between 102 and 439 μmol/min. and m² body surface area. On the average splanchnic FFA mobilization and uptake were about 30 and 60 per cent respectively of total FFA turnover rate. Significant positive correlations were found for the interrelationships between the three plasma FFA total and splanchnic transport parameters. Significant positive correlations were found between the three plasma TG “turnover rates” and total and splanchnic turnover of plasma FFA in subjects with normal plasma TG concentrations. Some patients with hypertriglyceridaemia fell outside the intervals of 99 per cent confidence of the regression analyses for the normo-triglyceridaemic subjects. This group had higher TG “turnover rates” than “expected” from plasma FFA turnover rates and may represent a distinctive group of hypertriglyceridaemia from the point of view of pathogenesis. It was concluded that all patients with hypertriglyceridaemia who were investigated had decreased “fractional turnover rates” of plasma TG indicating a decreased removal capacity which might be a primary cause of the hypertriglyceridaemia although inflow of plasma TG seemed to be an essential contributing factor in half the number of patients.     

The Effect of Clofibrate on the Elimination of Cholesterol as Bile Acids in Patients with Hyperlipoproteinaemia Type II and IV

Abstract. The turnover of ¹⁴C-cholic acid and ³H-chenode-oxycholic acid was studied in hyperlipaemic patients before and during treatment with clofibrate. - Before therapy the total formation of bile acids recorded for 6 patients with hyperlipoproteinnemia type Il (387± 70 mg/day, mean ± S.E.) was considerably less than that encountered for 6 patients with hyperlipoproteinaemia type IV (1 379 ± 221 mg/day). This difference was mainly due to a high synthesis of cholic acid in the latter patients. - The administration of clofibrate had no consistent effect on the half-life, pool size and turnover of the bile acids in the patients with type II lipoprotein pattern. The combined synthesis of cholic acid and chenodeoxycholic acid decreased in all patients with hyperlipoproteinaemia type IV and amounted on average to 549± 97 mg/day. The effect on the formation of chenodeoxycholic acid was insignificant but the turnover of cholic acid decreased from 1076± 243 to 333 ± 85 mg/day.     

Free fatty acid metabolism during fenofibrate treatment of the metabolic syndrome

OBJECTIVE: Our objective was to determine whether fenofibrate modifies the metabolism of nonesterified (free) fatty acids as a component of its triglyceride-lowering action in male patients with the metabolic syndrome. DESIGN: In a placebo-controlled trial lasting 16 weeks, patients were randomly assigned to fenofibrate (200 mg/d) or placebo for 8 weeks. They were then crossed over to placebo or treatment with fenofibrate for another 8 weeks. METHODS: Thirteen adult men had clinical characteristics of the metabolic syndrome that included atherogenic dyslipidemia, hypertension, elevated fasting glucose levels, or central obesity or a combination of these. They had measurements of plasma lipid and lipoprotein levels, postheparin lipase activities, and fasting concentrations and turnover rates of nonesterified fatty acids, as well as oral glucose tolerance testing with insulin and nonesterified fatty acid measurements. Levels of apolipoprotein C-II, C-III, and B were also measured, along with levels of low-density lipoprotein cholesterol in lipoprotein species. RESULTS: Fenofibrate therapy did not change plasma concentrations and turnover rates of nonesterified fatty acids. For fasting nonesterified fatty acids, the values (mean +/- SD) for placebo versus fenofibrate were 446 +/- 31 micromol/L versus 493 +/- 71 micromol/L, respectively (not significant); nonesterified fatty acid turnover rates were 336 +/- 36 micromol/min versus 334 +/- 42 micromol/min for placebo versus fenofibrate, respectively. Moreover, no changes were noted in fasting or postprandial levels of plasma glucose and insulin. Despite this lack of change, fenofibrate therapy reduced the plasma levels of triglyceride by 30% (305 +/- 143 mg/dL versus 206 +/- 90 mg/dL for placebo versus fenofibrate, respectively; P <.045), with a similar reduction in cholesterol levels of triglyceride-rich lipoproteins. Large low-density lipoprotein species were increased and small low-density lipoprotein species were decreased by fenofibrate therapy. Levels of apolipoprotein C-III were reduced significantly (P <.03), as were ratios of postheparin hepatic lipase to lipoprotein lipase (P <.05). CONCLUSION: Fenofibrate therapy markedly reduced plasma triglyceride levels. However, it did not lower concentrations or turnover rates of nonesterified fatty acids, nor did it change glucose or insulin responses to an oral glucose challenge. These findings indicate that fenofibrate modifies fatty acid metabolism either in the liver or in triglyceride-rich lipoproteins but not in adipose tissue. Multiple mechanisms are likely involved as a consequence of the action of fenofibrate to activate peroxisomal-proliferator-activated receptor alpha.     

Very low density lipoprotein overproduction in genetic forms of hypertriglyceridaemia

Abstract. Very low density lipoprotein kinetic parameters were compared in familial hypertriglyceridaemia and familial combined hyperlipidaemia, two distinct genetic forms of hypertriglyceridaemia. Very low density lipoprotein apoprotein B turnover rate was greater in hypertriglyceridaemic subjects with familial combined hyperlipidaemia (099±0–27 mg/kg/h; n = 5; P < 0005) and also in familial hypertriglyceridaemia (0–74±0–10; n = 6; P < 0–005) than in age and weight matched non-hyperlipidaemic controls (0–54±0–21; n = 6), suggesting that the hypertriglyceridaemia seen in both genetic disorders was due to very low density lipoprotein overproduction. Very low density lipoprotein apoprotein B turnover rate was greater in familial combined hyperlipidaemia than in familial hypertriglyceridaemia while plasma triglyceride turnover was higher in familial hypertriglyceridaemia. This disparity in the turnover rates of apoprotein B and triglyceride between these disorders was accompanied by a higher very low density lipoprotein triglyceride/apoprotein B ratio in familial hypertriglyceridaemia than in familial combined hyperlipidaemia ( P < 0001) and in normals ( P < 0–005).
The findings suggest that the hypertriglyceridaemia of familial combined hyperlipidaemia is due to overproduction of very low density lipoprotein of normal composition, while that of familial hypertriglyceridaemia is due to oversecretion of triglyceride-enriched very low density lipoprotein.     

Free fatty acid and carbohydrate metabolism of the working forearm muscle in type IV hyperlipoproteinaemia

Abstract. Substrate utilization of the working forearm was studied in nineteen patients with hypertriglyceridaemia (HLP) and compared to nineteen normolipidaemic (NLP) subjects, matched with regard to body weight, body height, intravenous glucose tolerance and age. Arterial-deep venous differences of oxygen, carbon dioxide, free fatty acids (FFA), glucose, lactate and pyruvate was measured. The fractional extraction and oxidation of fatty acids was assessed by intravenous infusion of albumin-bound [³H]palmitate and [¹⁴C]oleate. Measurements were made both in the postabsorptive state and after plasma FFA lowering by nicotinic acid. The HLP subjects had, before nicotinic acid, higher arterial concentrations, higher turnover rates of palmitate and oleate and higher plasma glycerol concentrations indicating a greater mobilization of FFA. However, the forearm extraction and oxidation of FFA as well as the calculated total body fatty acid oxidation was similar in HLP and NLP subjects. Nicotinic acid decreased arterial concentrations and turnover rates of FFA to the same extent in HLP and NLP groups, the effect being the same for palmitic and oleic acid. Fractional extraction both of palmitic and of oleic acid increased after nicotinic acid in the NLP but not in the HLP group. Plasma glycerol decrease after nicotinic acid was of the same magnitude in HLP and NLP groups. Thus, (1) an increased uptake of FFA in HLP subjects must occur in other tissues than skeletal muscle and with another fate of the fatty acids than oxidation. The explanation might be an increased incorporation of fatty acids into triglycerides which are subsequently secreted from the liver. (2) The impaired triglyceride removal in skeletal muscle which has been found in HLP subjects is more likely due to an impaired lipolytic activity than to an abnormality in uptake and utilization of hydrolysed fatty acids. No abnormalities in carbohydrate metabolism were found in these HLP subjects with normal glucose tolerance.     

Ceftriaxone disposition in open-heart surgery patients.

The effects of cardiopulmonary bypass (CPB) with hypothermia and systemic heparinization on ceftriaxone disposition were evaluated in seven male patients. A bolus dose of drug (14 mg/kg of body weight) was given, and blood and urine specimens were collected before, during, and after CPB for 96 h. Creatinine, albumin, and total and free ceftriaxone concentrations in plasma were measured. The ceftriaxone free fraction (ff) in vitro was estimated by equilibrium dialysis, and the in vivo ff was obtained by the ratio of renal clearance due to filtration to creatinine clearance. Pharmacokinetic parameters were based on concentrations of total drug and free drug. Albumin decreased from 3.10 +/- 0.29 g/dl presurgery to 1.42 +/- 0.17 g/dl and recovered to 2.46 +/- 0.26 g/dl on postoperative day 4. CPB markedly increased the in vitro ff, which was reversed by protamine post-CPB (ff pre-CPB, 0.15 +/- 0.01; during CPB, 0.53 +/- 0.20; post-CPB, 0.16 +/- 0.02). The in vitro ff exceeded the in vivo ff (0.53 +/- 0.20 versus 0.24 +/- 0.07), probably due to continued free fatty acid release caused by heparin during dialysis. Clearances based on free drug decreased, and the renal clearance due to filtration increased (7.6 +/- 2.8 versus 15.0 +/- 4.5 ml/min) while the creatinine clearance decreased (114 +/- 29 versus 72 +/- 28 ml/min) during CPB. Diminished binding owing to low albumin and free fatty acids explain this behavior. Lower binding also increased the volume of distribution (154 +/- 41 ml/kg) and extended the half-life (15 +/- 6 h). In summary, ceftriaxone disposition was significantly altered by CPB, resulting in marked increases in free drug concentrations, half-life, and volume of distribution and in decreased intrinsic clearance.     

Effect of pindolol, a beta-adrenoceptor blocking agent, on lipid metabolism

Pindolol, a beta-adrenoceptor blocking agent, was administered to rats to determine the effects of the drug on lipid and lipoprotein in plasma and tissues. The drug caused significant reductions in plasma triglyceride, free fatty acid and very low density lipoprotein. As for lipoprotein lipase activity, the drug produced varying effects; an increase in the heart and a reduction in the adipose tissue. No significant changes in plasma cholesterol, low density lipoprotein and high density lipoprotein cholesterol were observed. The disturbance of growth was noted following pindolol treatment.     

Glucagon regulation of plasma ketone body concentration in human diabetes.

The present study was designed to test the hypothesis that physiological concentrations of glucagon may increase plasma ketone body concentration when sufficient free fatty acid substrate is available to support hepatic ketogenesis. Physiological elevations of plasma glucagon concentration were produced by a constant infusion of hormone, and increased plasma-free fatty acid availability was produced by simultaneous heparin injection to induce intravascular lipolysis. In the five insulin-dependent subjects studied, when plasma glucagon concentration remained at the normal basal level of 72+/-14 pg/ml during control saline infusion, the heparin-induced increase in free fatty acid availability resulted in approximately a 20% increase in plasma ketone body concentration. In contrast, when plasma glucagon concentration was elevated by hormone infusion to the physiological level of 215+/-35 pg/ml, the heparin-induced increases in free fatty acid availability resulted in approximately an 80% increase in plasma ketone body concentration. These results suggest that physiological elevations in plasma glucagon concentration may augment ketonemia in diabetic man when simultaneous elevations in plasma-free fatty acid arepresent.     

Clofibrate displaces warfarin from plasma proteins in man: an example of a pure displacement interaction.

Clofibrate is known to potentiate the anticoagulant effect of warfarin during chronic administration. We examined the disposition of racemic warfarin in four healthy volunteers before and during clofibrate coadministration using an intravenous-continuous oral sequence of warfarin administration. An interaction between warfarin and clofibrate, evidenced by longer prothrombin and prothrombin-proconvertin times, was seen in all four subjects. Clofibrate caused a displacement of warfarin from plasma protein binding sites, with a 13% increase in the free drug fraction in plasma. As predicted from theoretical considerations, this displacement resulted in a small (18%) increase in the steady-state volume of distribution, and an increase in total plasma clearance, which, for warfarin, is independent on the free fraction of drug in plasma. The net effect of these changes is that the free concentration of warfarin was not changed during clofibrate coadministration, although total plasma concentrations were lower. This study documents the occurrence in man of a displacement pharmacokinetic interaction between clofibrate and warfarin. However, this pharmacokinetic interaction does not account for the clinical interaction between the two drugs, since free warfarin concentrations are unchanged.