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Unlabelled: Radiolabeled fatty acids such as 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) have unique metabolic properties of potential use as myocardial perfusion tracers. Accordingly, we compared the in vivo pattern of uptake of BMIPP and 201Tl in hypoperfused rabbit myocardium., Methods: Animals were intubated, ventilated and their arterial pressures monitored. A left thoracotomy was performed. After ligation of a major branch of the circumflex artery, an intravenous injection of BMIPP or BMIPP/201TI was given. Radiolabeled microspheres were used to document the area of risk. After the circulation period, the animals were killed. Tracer deposition within the hearts was determined by either dual-tracer autoradiography (Protocol I) or by segmental tissue analysis (Protocol II)., Results: Dual-tracer autoradiographic activity profiles for BMIPP were comparable to those of 201TI. Moreover, the two tracers yielded similar values for normal-to-defect contrast and defect size. The myocardial activity concentration of BMIPP for both protocols correlated strongly with coronary blood flow and compared favorably with 201TI., Conclusion: BMIPP and 201TI accurately delineate areas of hypoperfusion distal to a coronary occlusion. Therefore, differences in the myocardial distribution of BMIPP and 201TI in clinical studies may be related to cellular fatty acid metabolism.

The present study was undertaken to determine the potential diagnostic value of 123I-BMIPP scintigraphy for the detection of altered myocardial fatty acid metabolism in patients with unstable angina. Both myocardial metabolic imaging with 123I-BMIPP and perfusion imaging with 99mTc-sestamibi were performed at rest in 28 patients with unstable angina in the pain-free state. The regional uptakes of 123I-BMIPP or 99mTc-sestamibi were scored semiquantitatively (0 = normal, 4 = no activity) and compared with the coronary arteriographic findings. Decreased uptakes of 123I-BMIPP were observed in 18 patients, and 11 patients had abnormal 99mTc-sestamibi images. Defect scores of 123I-BMIPP were larger than those of 99mTc-sestamibi (7.8 +/- 2.1 vs. 5.2 +/- 1.9, p < 0.01). The sensitivity for the detection of patients with unstable angina was higher in 123I-BMIPP than in 99mTc-sestamibi (77% vs. 45%, p < 0.01). The site of the decreased 123I-BMIPP uptake corresponded to the most stenotic coronary artery lesion in all patients. Fatty acid metabolic imaging with 123I-BMIPP was more sensitive for detecting myocardial ischemia than perfusion imaging with 99mTc-sestamibi. 123I-BMIPP may be a clue to define the culprit lesion in unstable angina and be helpful to decide the best treatment and guide coronary angioplasty.

We estimated the systemic and left ventricular (LV) regional myocardial distribution of 123I-BMIPP (beta-methyl-p-iodophenyl-pentadecanoic-acid) in normal subjects (n = 13, mean age 43.9). In planar studies, the count ratios of heart, lung and liver to mediastinum were 2.63, 1.28 and 3.80 in the early images, and 2.23, 1.20 and 2.26 in the delayed images, respectively. The uptake in liver was almost identical with that in heart in the delayed images. In SPECT studies, the regional relative counts in anterior, septal, posterior and lateral LV walls were 100, 98, 96 and 108 (%) in the initial images, and 100, 98, 99 and 107 (%) in the delayed images, respectively. The regional relative uptake was significantly higher in the lateral wall than those in the other parts of LV walls in both images. The relative counts in the basal, mid- and apical portions were 100, 111 and 87 (%) in the initial images, and 100, 113, 92 (%) in the delayed images, respectively. These results suggest that the myocardial regional distribution of BMIPP is not always uniform even in normal subjects. Thus, it is necessary to interpret with caution in the light of these findings, especially for detect in a myocardial lesion in an early phase of cardiomyopathy or a mild myocardial ischemia.

Unlabelled: Increased clinical use of 123I-labeled 15-(p-iodophenyl)-3-(R,S)-methyl- pentadecanoic acid ([123I]BMIPP) revealed discordance between BMIPP uptake and that of perfusion agents, which was inexplicable due to the uncertainty of its myocardial metabolism. This study clarifies the metabolic fate of BMIPP and its relation to substrates in isolated rat hearts., Methods: Rat hearts were perfused with 5 mmole/liter HEPES buffer containing various energy substrates and 1% bovine serum albumin. The buffer was recirculated for 4 hr after bolus injection of [123I]BMIPP. Heart time-activity curves were monitored externally. After perfusion, the radioactivity in the heart and recirculated buffer was measured. The metabolites in the buffer were then extracted and analyzed by HPLC and TLC., Results: when 0.4 mmole/liter oleate was the energy substrate, more than eight radioactive BMIPP metabolites were detected. The metabolites in the coronary effluent depended on the energy substrate in the buffer. The radioactivity in the heart at the end of the perfusion period was significantly higher when 0.4 mmole/liter oleate (28.0% +/- 1.2% ID/g, mean +/- s.e.m.) or 10 mmole/liter glucose with 25 U/liter insulin (43.9% +/- 2.2% ID/g) were the substrates compared to when 5 mmole/liter acetate (8.5% +/- 0.4% ID/g) or 0.4 mmole/liter cold BMIPP (6.2% +/- 0.3% ID/g) were the substrates. The distribution of metabolites suggests that oleate stimulated both alpha and beta oxidations, whereas glucose with insulin inhibited both. Acetate also stimulated alpha oxidation but not beta oxidation. Cold BMIPP strongly inhibited both alpha- and beta-oxidations, and little alpha oxidation occurred compared to beta-oxidation., Conclusion: These results suggest that [123I]BMIPP is metabolized in the myocardium and the metabolism is closely related to myocardial carbohydrate utilization.

Iodine-123 beta-methyl iodophenylpentadecanoic acid (BMIPP) has been used for evaluating myocardial fatty acid metabolism in vivo. The whole body BMIPP imaging was acquired in 26 patients (11 with HCM, 11 with CAD and 4 with DCM) to calculate % uptake in the myocardium and to correlate its uptake with biochemical data, including blood sugar (BS), nonesterified fatty acid (NEFA) and insulin in the blood. BMIPP was administered at rest with overnight fasting state, and the anterior and posterior whole body imaging was performed one hour later. The background corrected whole myocardial counts were calculated to obtain %BMIPP uptake. In addition, the heart to mediastinum count ratio (H/M ratio) was calculated from the mean counts in the heart and the upper mediastinum in the anterior view. The %BMIPP uptake was 3.70 +/- 1.22% and H/M ratio was 2.30 +/- 0.23. The patients with DCM showed higher %BMIPP uptake values (DCM = 5.58 +/- 0.67% vs. CAD = 3.09 +/- 0.97% and HCM = 3.63 +/- 0.86%, both p < 0.01), but similar values of H/M ratio with other patients (DCM = 2.43 +/- 0.20, CAD = 2.22 +/- 0.25 and HCM = 2.32 +/- 0.20). Although the biochemical data varied at the time of the tracer administration, they were not significantly correlated with the %BMIPP uptake or H/M ratio. However, there was a significant correlation between %BMIPP uptake and H/M ratio with the correlation coefficient of 0.80 (p < 0.001). We conclude that the myocardial uptake of BMIPP is not influenced by the plasma substrate level under the fasting state.

To elucidate the metabolism of free fatty acid in the myocardium of hypertrophic cardiomyopathy (HCM), SPET was performed with 123I-15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP), an analogue of free fatty acid, and with 201Tl in nine patients with HCM and eight healthy volunteers who acted as controls. For quantitative analysis of the apical area, a radial long-axis tomogram was reconstructed every 6 degrees after short-axis tomography. The relative regional uptake (RRU, %) in each segment was obtained by normalizing to the maximal value among all segments. The 3-h washout rate was calculated both for BMIPP and for 201Tl. The ratio of the RRU of BMIPP to that of 201Tl was significantly lower in the apical and antero-septal regions compared with other walls (P < 0.01) in the patients with HCM, whereas uptake of both BMIPP and 201Tl in the controls was homogeneous and there was a significant correlation between them. The coefficient of variation (CV) in all segments in the HCM patients was significantly higher (P < 0.01) than that of the controls both BMIPP and 201Tl, indicating inhomogeneous uptake of BMIPP in the HCM patients. The washout rate of BMIPP over 3 h was significantly higher in the patients with HCM (mean +/- S.D. 26.3 +/- 7.3%) than the controls (18.3 +/- 7.5%, P < 0.05). The ratio of segmental washout rate of BMIPP to that of 201Tl in the HCM patients was increased, especially in the septum and apex.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared the absorption of eicosapentaenoic (EPA, 20:5n-3), docosahexaenoic (DHA, 22:6n-3), and decanoic acids in mesenteric lymph duct-cannulated rats following intragastric administration of two oils with different intramolecular triacylglycerol structures. One oil had a specific triacylglycerol structure with EPA and DHA located in the sn-2 position and decanoic acid in the sn-1 and sn-3 positions (specific M-n3-M) whereas the other oil had a random fatty acid distribution (random M-n3-M). The mol% (mol/100 mol total fatty acids) of fatty acids in the two oils was similar, with approximately 66 mol% of decanoic acid and 22 mol% of EPA and DHA. The lymphatic transport (microgram/min) of EPA and DHA as well as the mol% in the total lymph lipids were significantly (both P < 0.01) increased following intragastric administration of specific M-n3-M compared with random M-n3-M. The mol% of decanoic acid in the total lymph lipids was significantly (P < 0.01) higher after random M-n3-M compared with specific M-n3-M but the transport (microgram/min) of decanoic acid was not significantly different. We conclude that under our experimental conditions specific M-n3-M with EPA and DHA predominantly in the sn-2 position of the triacylglycerols was a more readily absorbed source of EPA and DHA and in this context should be investigated further for the potential use in clinical nutrition.

The aim of this study was to determine the extent and location of damaged myocardial areas in senescent rats. The viability of myocardial cells was evaluated in virgin young (4 months old) and aged (29 months old) female Wistar rats by analysing the uptake of a slowly metabolisable radiolabelled fatty acid analogue, 15-p-iodophenyl-beta-methylpentadecanoic acid (IMPPA). The biodistribution of IMPPA was measured in various organs, and regional myocardial uptake was specifically assessed using quantitative autoradiography. Myocardial enzymatic activity and DNA content were also evaluated with nitro blue tetrazolium (NBT) and propidium iodide (PI) staining, respectively. In senescent rats, cardiac and renal IMPPA uptake showed a significant (50%) reduction compared with young adult rats and the uptake was not significantly changed in the liver, spleen, lungs, and skeletal muscle. Total ventricular NBT staining and IMPPA uptake were almost homogeneous in young adult rats, whereas they were very heterogeneous in aged rats. In the latter, approximately 11% of the total ventricular volume showed a significantly decreased (by 60% or more) IMPPA uptake compared with normal values, and this reduction was greater in ventricle base than in apex. The myocardial areas unlabelled or poorly labelled by IMPPA represented 4, 5, 6, and 21% of the right ventricular, left ventricular epicardial, septal, and left ventricular endocardial volume, respectively, and were poorly stained with NBT. In some of these areas, PI staining indicated the presence of living cells unable to pick up NBT staining. In conclusion, in young adult rats, no myocardial lesions were observed using three different labelling techniques.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolic disposition and elimination process of the anhydride co-polymer poly[1,3-bis(p-carboxy-phenoxypropane):sebacic acid] 20:80 [P(CPP:Sa)20:80] implanted in the rat brain was studied. Two polymers were prepared, one with [14C]SA and unlabelled CPP, and the other co-polymer with [14C]CPP and unlabelled SA. With these two polymers we were able to study the metabolic disposition of each monomer after polymer degradation. Polymer wafers loaded with N,N-bis(2-chloroethyl)-N-nitrosourea or without the drug were implanted in the rat brain. For the rats implanted with the [14C]SA-labelled polymer, approximately 40% of the radioactivity was found in the expired CO2, 10% in the urine, about 2% in the faeces and about 10% remained in the device 7 d after implantation. On the other hand, only 4% of the [14C]CPP monomer was eliminated by urine and faeces during this period. The drug-loaded polymer degraded faster than the blank polymer. This study supports the theory that the polymer is a biodegradable material that can be used for the direct and specific delivery of drugs into a targeted organ and can provide continued release of drugs over a period of time.

Intracranial studies to analyze the degradation kinetics of the bioerodible polymer poly[bis(p-carboxyphenoxy)propane-sebacic acid] [p(CPP-SA) 20:80] copolymer wafers were conducted in a rat model. Rats were separated into four groups: those receiving 1) polymer, 2) polymer loaded with the chemotherapeutic agent BCNU, 3) drug-loaded polymer with previous tumor implantation, and 4) polymer and an absorbable hemostatic material. A polymer wafer was surgically implanted into the brain of each animal. Residual polymer was harvested at varying times for chromatographic analysis. In vitro effects of pH, mixing, and water availability on degradation were also studied. The results of in vitro and in vivo studies were compared to understand the behavior of polymers in a clinical setting. We found that degradation of p(CPP-SA) initially occurred more slowly in vivo than in vitro. The presence of BCNU, tumor, and absorbable hemostatic material did not affect the ultimate time of polymer degradation in vivo, and the intrinsic polymer degradation time of 1 mm thick p(CPP-SA) 20:80 disks in vivo was 6-8 weeks.

The effects on oxygen consumption and carbon dioxide production of a constant intravenous infusion of 0.15 g of disodium sebacate (Sb), the sodic salt of a medium-chain dicarboxylic acid with 10 carbon atoms, per kilogram of body weight per hour over 5 hours and a 50% mixture of medium- and long-chain triglycerides (MCT/LCT) were compared in 10 healthy men. Oxygen consumption and carbon dioxide production were measured by indirect calorimetry. Mean oxygen consumption was about 19% higher than the basal oxygen consumption at the end of MCT/LCT infusion but was only 5% higher than the basal oxygen consumption when Sb was infused. There was an eightfold increase in plasma beta-hydroxybutyrate and acetoacetate concentrations and a threefold increase in serum insulin levels during MCT/LCT infusion, but no significant change in ketone bodies and insulin from basal values was observed during and after Sb infusion. Pharmacokinetic parameters were also computed, showing an average apparent volume of distribution of 167 mL/kg of body weight for MCTs and 112 mL/kg of body weight for Sb. The t1/2 of MCTs was 50 minutes and that of Sb was 78 minutes. Urinary excretion of Sb and its beta-oxidative by-product, suberic acid, globally accounted for 48% of the given amount of Sb. In spite of its urinary loss and slower tissue uptake compared with MCTs, Sb avoided ketone body formation or elevation in insulin levels and did not induce a significant increase in oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Male Fischer-344 rats administered a single intraperitoneal dose of perfluoro-n-octanoic acid (PFOA) or perfluoro-n-decanoic acid (PFDA) display a similar "wasting toxicity" characteristic of perfluorocarboxylic acids, with marked differences in temporal expression. Food/water consumption and urine output were monitored daily in PFOA-treated, PFDA-treated, and control rats. Fluorine-19 nuclear magnetic resonance (NMR) spectroscopy was used to monitor these fluorocarbons and possible fluoro metabolites in vivo, and to correlate differences in elimination with differences in effective toxicity. The data reveal a prolonged hypophagic response to PFDA and a more acute but transient response associated with PFOA treatment. PFOA causes a greater decline in food consumption than PFDA within the first 24 h postdose. PFOA-treated rats also show a ca. 2.5-fold increase in urine output on day 1, with only a slight increase in water consumption. In contrast to PFDA, PFOA-treated rats recover from hypophagia within 8 days. Fluorine-19 NMR spectra of various bodily fluids and liver in vivo display resonances of the parent PFOA or PFDA compounds and do not reveal any evidence of metabolism. Inorganic fluoride from dietary sources is detected in urine from both exposed and control rats. Differences in the route of excretion of PFOA vs PFDA are apparent from the spectral signal-to-noise ratio. The data suggest that PFOA is more readily excreted in the urine while PFDA is preferentially carried in bile. These apparent differences in elimination may account for their observed differences in effective toxicity. The acute transient toxicity and higher LD50 associated with PFOA may result from its rapid renal clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Sebacic acid (C10), a saturated, straight-chain dicarboxylic acid with 10 carbon atoms in disodic salt form, was given intravenously to two groups of healthy male volunteers in order to evaluate its possible use in total parenteral nutrition. The first group, composed of six subjects, received 1000 mg of sebacate as a bolus; six other subjects (second group) received 10 g of sebacate dissolved in 500 mL of double-distilled water at an infusion rate of 3.33 g/h over 3 hours. The serum sebacate data for each subject were analyzed by computer, using biexponential fit corresponding to a 2-compartment open model. The distribution half-life (t1/2) was 0.34 +/- 0.06 hour and the elimination phase was rather rapid (Ke = 2.10 +/- 0.38/h); the volume of the central compartment was 2.79 +/- 0.54 L and the volume of tissue compartment 3.72 +/- 0.14 L. These data showed a good tissue fixation of sebacate. The plasma clearance was evaluated to be 5.96 +/- 2.19 L/h and the renal clearance was 19.22 +/- 10.69 L/h, indicating that a tubular secretion of C10 takes place. The serum concentration of sebacate raised to the maximal value at the end of the infusion (180 minutes), corresponded to 480.50 +/- 43.02 micrograms/mL. Respiratory and metabolic parameters were evaluated by indirect calorimetry from the beginning of the infusion for 210 minutes. The O2 consumption (VO2 mL/min per square meter) remained essentially unchanged throughout the experiment (from 154.3 +/- 28.3 at 0 to 155.3 +/- 39.5 at time 180 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Disodium sebacate is a 10-carbon-atom dicarboxylic acid, proposed as substrate for parenteral nutrition. We investigated its pharmacokinetic profile and thermogenic effect during a short-time infusion (5 h at 10 g/h) in 7 male volunteers. Sebacate in serum and urine was measured by high-performance liquid chromatography. A single-compartment model with two linear elimination routes was fitted. Metabolic measurements (VO2, VCO2, respiratory quotient, metabolic rate) were continuously performed for 8 h (5 h during and 3 h after the infusion) by a canopy indirect calorimeter. The apparent volume of distribution of sebacate was 8.39 +/- 0.69 liters, and the plasma fractional removal rate constant was 0.0086 +/- 0.00077 min-1. The average half-life and plasma clearance were 80.6 min and 72 ml/min, respectively. The increase in metabolic rate, the decrease in respiratory quotient and the changes in ketone body, glucagon and insulin levels during the infusion were not significant. 24-hour catecholamine excretion was within normal limits. Calories administered by sebacate seem to be available for utilization without relevant metabolic side effects.

The present study investigates the metabolic disposition of sebacic acid in rats. Three groups of experimental animals received different doses of disodium sebacate with 25 microCi of 14C-labeled molecule by intravenous injection. In the first group radioactivity plasma elimination curves were examined for two administered doses (80 and 160 mg). In the second group, expired 14CO2, urine tracer and feces tracer were counted after intravenous administration of 160 mg of sebacate. The animals of the third group were sacrificed at different times after intravenous administration of 160 mg of sebacate, and tracer elimination curves were obtained for several organs. The plasma half-life of sebacate is 38.71 min; about 35% of the administered tracer was excreted in the urine as unchanged sebacate; about 25% was eliminated as 14CO2 in expired air. Disposition of sebacate was complete within 4 h of administration. The sebacate half-life is longest in adipose tissue (135 min) and in liver (74 min), sites of likely transformation. In all other organs examined, the sebacate half-life is similar to that in plasma.

The purpose of the present research was to test the ion pair absorption hypothesis with respect to the topical route of drug delivery. The experiment consisted of preparing various lidocaine-n-alkanoate ion pairs, then characterizing them by proton magnetic resonance spectroscopy, elemental analysis and conductivity. Percutaneous absorption studies through excised hairless mouse skin were carried out using ethanolic solution of radiolabeled 14C-lidocaine-octanoate, 14C-lidocaine-decanoate and 14C-lidocaine-dodecanoate. Studies were conducted under steady-state conditions using Bronaugh's flow-through apparatus and normal saline as the receptor fluid. Ethanolic solution of a lidocaine base served as a control. The apparent differences in flux between lidocaine and the various ion pairs were statistically significant (p less than 0.05). The differences among the fluxes of the various ion pairs were not statistically significant (p greater than 0.05), nor were the differences in lag times (p greater than 0.05). The difference between the flux values of lidocaine-1-14C-dodecanoate and 14C-lidocaine-dodecanoate infers that lidocaine-dodecanoate did not cross the excised, full-thickness, hairless mouse skin as an intact 1:1 ion pair. The formation of weakly associated ion pairs was suggested by the apparent low-association constants (Ka = 15-17 liters/mol) obtained at 25 degrees C in methanol by conductometric analysis.

How variable is the deposition of inhaled methacholine (MCH) in the respiratory tract during a challenge test? Does this variability contribute to the variability of airway responsiveness? To examine these questions we estimated the deposition of polydisperse MCH droplets by measuring the deposition of surrogate diethylhexyl sebacate (DEHS) droplets that were similar in size (1.5 microns) but monodisperse. Light scattering photometry and flow measurements were used to compute inspired and expired DEHS particle number. Deposition of DEHS during 4 breaths was measured twice at baseline and after every dose of MCH during an abbreviated challenge test in 16 subjects. Deposition was then compared with reactivity. Reactivity to MCH was expressed as the dose-response slope; it was calculated as percent final change in FEV1/cumulative dose MCH inhaled. Dose-response slopes ranged from zero (nonreactive) to -15.0 (very reactive) %/mumol (mean -3.2 +/- 5.3 SD). Seven subjects had a 20% or greater decrement in FEV1 after their highest MCH dose. Baseline DEHS deposition, which ranged from 66 to 84% (mean 77 +/- 5 SD), was not significantly different between responders and nonresponders and was not a significant predictor of the dose-response slope. Reactivity was significantly associated with an increase in deposition produced by MCH (p less than 0.007). This increase was small, however (relative change less than 7%), so that the effect on the deposited dose of MCH was minimal. We conclude that, with the breathing pattern used, individual differences in DEHS (and MCH) deposition were small and contributed little to intersubject variability of responsiveness to inhaled MCH.

In order to better ascertain its possible use as an alternative fuel substrate in total parenteral nutrition, sebacate (Sb) metabolism was studied in seven overnight-fasting healthy male volunteers, who received a constant iv infusion (99 mmoles over 8 hours) of disodium sebacate. Sb oxidation rate was determined using an isotopic sebacate (disodic salt of (1-10)14C-sebacic acid) infusion (100 mu Ci from the fourth to the eighth hour of the cold sebacate infusion). Blood samples were collected during and after sebacate infusion at intervals of 30 minutes and Sb serum concentrations were determined by high performance liquid chromatography. Excreted radioactivity (mu Ci/min) was measured by bubbling the expired air into an apparatus containing 3 mEq hyamine to trap CO2 from a 20-L Douglas-bag. CO2 production and O2 consumption were measured before and at 4 and 8 hours after starting the infusion. Twenty-four hour nitrogen excretion with urine was obtained. The RQ and the percent of calories derived from lipid oxidation were calculated by indirect calorimetry. The Sb serum level at the plateau phase was (mean +/- SD) 4.54 +/- 0.71 mumole/mL, the overall rate of tissue uptake was 180.89 +/- 4.50 mumole/min, and the percent oxidation was 6.14 +/- 0.44%. At the end of Sb infusion the RQ dropped to 0.839 +/- 0.043, the percent of calories due to sebacate oxidation was 1.59 +/- 0.52%, and the calories derived from lipids increased to 37.77 +/- 12.90%. These data show that a definite amount of the sebacate infused is oxidized in human tissues.

The elimination, tissue distribution, and metabolism of [1-14C]PFDA were examined in male and female rats for 28 days after a single ip dose (9.4 mumol/kg, 5 mg/kg). A sex difference in the fecal elimination of perfluorodecanoic acid (PFDA) was observed with 51 and 24% of the administered 14C being recovered in the feces of male and female rats, respectively, by 28 days post-treatment. The cumulative excretion of PFDA-derived 14C in the urine in 28 days was less than 5% of the administered dose in both sexes. The sex-related difference in the rate of fecal elimination resulted in the observed difference in whole body elimination t1/2 of PFDA in males (t1/2 = 23 days) and females (t1/2 = 45 days). The liver contained the highest concentration of PFDA-derived 14C in both males and females, followed by the plasma and kidneys. The heart, fat pads, testes, and gastrocnemius muscle of males, and the ovaries of females contained much lower concentrations of PFDA. The reason for the high percentage of the ip dose of [1-14C]PFDA in the liver (53% males and 41% females, 2 hr post-treatment) was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that approximately 25% of the [14C]PFDA in the perfusate was extracted by the liver in a single pass. The basis for the sex difference in fecal elimination of PFDA does not appear to be due to a sex difference in biliary excretion. In a 6-hr period, male and female rats with kidneys ligated eliminated essentially the same percentage dose of [14C]PFDA into bile. We had hypothesized that the persistence of PFDA in rats was due to formation of a PFDA-containing lipid (i.e., a [14C]PFDA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid). However, no evidence that PFDA is conjugated to form persistent hybrid lipids was obtained, nor were polar metabolites of PFDA detected in urine or bile. In addition, daily urinary excretion of fluoride in male and female rats before and after PFDA treatment was similar, suggesting that the parent compound is not defluorinated. Thus, the disposition of PFDA in male and female rats is characterized by an apparent lack of biotransformation.

Tissue distribution, metabolism, and excretion of perfluorodecanoic acid (PFDA) after a single intraperitoneal dose (20 mg/kg) were studied in female and male Wistar rats. PFDA accumulated in the serum and tissues of the rats. In the serum, more than 99% of PFDA was bound by the serum proteins. In the liver, anionic and esterified PFDA were detected. Metabolic oxidation of PFDA was not observed. PFDA was not excreted in urine either by females or males during 14 days after the administration. At the same time, about 0.5% of the administered PFDA dose was excreted daily in the faeces by both sexes. In spite of the analogical structure with perfluorooctanoic acid (PFOA), which is rapidly eliminated in urine by the female rats, PFDA accumulated similarly in females and males. The reduced elimination of PFDA partially explains its greater toxicity to rats in comparison with PFOA.

Two methods are described for determination of octanoic and decanoic acids in plasma and brain homogenate by "high-performance" liquid chromatography with ultraviolet detection. Analysis of the underivatized acids had a detection limit of only 50 mg/L, but formation of the p-bromophenacyl ester increased the sensitivity by 100-fold, to a detection limit of 0.5 mg/L. The latter procedure gave interassay coefficients of variation of 4.1% and 4.8% for octanoic and decanoic acids, respectively. The corresponding intra-assay values were 3.95% and 4.7% (n = 6). The derivative method, applied to samples of plasma from children receiving a medium-chain triglyceride (MCT) diet, gave values in agreement with results by gas-liquid chromatography. Results have also been obtained for samples from mice, either treated with the medium-chain triglyceride diet or given infusions of sodium octanoate.