Maximum Excretion Rate Research Articles

Analysis program based on finite element method, MULTI(FEM), for evaluation of dose‐dependent local disposition of drug in liver

A curve‐fitting program based on the Finite Element Method, MULTI(FEM), was developed to model nonlinear local disposition of a drug in the liver under non‐steady‐state conditions. The program was written in FORTRAN on an IBM‐compatible personal computer. The validity of MULTI(FEM) was confirmed by analyzing the outflow kinetics of oxacillin (a model drug) following a pulse input to isolated, perfused rat livers, according to both linear and nonlinear dispersion models. Four dose levels (300, 1000, 3000, and 5000 µg) of oxacillin were administered to observe the dose‐dependency in the hepatic local disposition. First, the individual outflow time‐profiles at the same dose were averaged, and the average time‐profile was analyzed by MULTI(FEM) based on linear dispersion models to yield a single curve fit. The fitted parameters at each dose level were compared with parameters estimated using MULTI(FILT), a program based on fast inverse Laplace transform, to analyze linear pharma‐cokinetics. The estimated parameters by MULTI(FEM) were in good agreement with those by MULTI(FILT). The apparent elimination rate constant (ke) decreased with an increase in dose, whereas other parameters showed no discernible dependency on an increase of dose. Second, the average outflow time‐profiles at the four dose levels were simultaneously analyzed by MULTI(FEM) based on dispersion models featuring Michaelis–Menten elimination. The outflow time‐profiles of oxacillin were well approximated by a two‐compartment dispersion model with central Michaelis–Menten elimination. The maximum elimination rate constant (Vmax) and the Michaelis constant (Km) were estimated to be 1520 µg/mL/min and 41.3 µg/mL, respectively. Thus, the capability of MULTI(FEM) was demonstrated in evaluating capacity‐limited local disposition in the liver.

Production and elimination of hyaluronan in rheumatoid arthritis patients: estimation with a loading test

Objective: To evaluate the benefit of determining the maximal elimination rate (V max) and the endogenous production of hyaluronan (HYA) in relation to the basal HYA concentration (c 0) in rheumatoid arthritis (RA) patients; and to evaluate the compatibility of a new model for HYA kinetics, taking renal elimination into separate account in the overall clearance of HYA from the blood. Methods: The calculations of production and elimination of HYA were based on the HYA loading test, which was performed in 21 patients with RA and 15 healthy controls. A blood sample was drawn before the loading test, followed by an intravenous (IV) injection of HYA as a single bolus dose of 7.5 mg. Blood samples were taken regularly during the next 60 minutes. A theoretical model with computational analysis of the data collected was used for calculating HYA production and elimination. Results: Patients with RA had significantly higher c 0 than healthy controls, although in 10 of 21 patients co was within the normal range. The RA patients also had higher V max than healthy controls, but the difference was not significant. The calculated production of HYA was increased in RA patients ( P = .001) and correlated with c 0 ( P < .0001). The new model for HYA kinetics, in which the renal elimination was taken separately into account, proved to be more compatible than the previous model. Conclusion: The HYA loading test can help determine whether the increasedserum level of HYA in RA patients is due to a high production or reduced elimination of HYA or both.

The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics.

The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed. The genotype of CYP2C9 (Arg144/Cys, Ile359/Leu) and CYP2C19(*1, *2 or *3) in 134 Japanese adult patients with epilepsy treated with PHT were determined, and their serum concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) enantiomers, being major metabolites of PHT, were measured. A population pharmacokinetic analysis (NONMEM analysis) was performed to evaluate whether genetic polymorphism of CYP2C9/19 affects the clinical use of PHT by using the 336 dose-serum concentration data. The mean maximal elimination rate (Vmax) was 42% lower in the heterozygote for Leu359 allele in CYP2C9, and the mean Michaelis-Menten constants (Km) in the heterozygous extensive metabolizers and the poor metabolizers of CYP2C19 were 22 and 54%, respectively, higher than those without the mutations in CYP2C9/19 genes. (R)- and (S)-p-HPPH/PHT ratios were lower in patients with mutations in CYP2C9 or CYP2C19 gene than those in patients without mutations. Although the hydroxylation capacity of PHT was impaired with mutations of CYP2C9/19, the impairment was greater for CYP2C9. In view of the clinical use of PHT, two important conclusions were derived from this population study. First, the serum PHT concentration in patients with the Leu359 allele in CYP2C9 would increase dramatically even at lower daily doses. Second, the patients with CYP2C19 mutations should be treated carefully at higher daily doses of PHT.

Influence of indocyanine green on plasma disappearance and biliary excretion of a synthetic thrombin inhibitor of the 3-amidinophenyl-alanine piperazide-type in rats.

The pharmacokinetics of a number of synthetic peptidomimetic thrombin inhibitors is determined by extensive hepatic elimination. The objective was to further characterize the disposition in vivo of Pefa 1023, a novel 3-amidinophenylalanine piperazide-type thrombin inhibitor, by influencing the hepatic handling with indocyanine green (ICG), which is actively taken up by the liver. Pefa 1023 was administered intravenously to bile duct-cannulated rats, either alone or in combination with ICG. The concentrations of Pefa 1023 in blood plasma and bile were measured by a bioassay (thrombin clotting time), concentrations of indocyanine green were measured spectrophotometrically. ICG (10 mg/kg i.v. 15 min prior to or simultaneously with Pefa 1023) markedly influenced the plasma level and biliary excretion rate of the thrombin inhibitor Pefa 1023 given in a dose of 1 mg/kg i.v. The plasma level was more than twice that of the control, the maximum biliary excretion rate about one third and the fraction of dose excreted in bile about two thirds. The anionic dye ICG is able to interfere with the hepatic handling of a cationic, amidinophenylalanine piperazide-type thrombin inhibitor with the consequence of reduced hepatic clearance leading to higher plasma levels and lower biliary excretion of the latter.

Pharmacokinetic analysis program based on tank-in-series model, MULTI(TIS), for evaluation of capacity-limited local disposition.

A pharmacokinetic analysis program based on a tank-in-series model, MULTI(TIS), was developed for the evaluation of dose-dependency in the local disposition of a drug. The program written in FORTRAN was constructed by expanding MULTI(RUNGE). The reliability of MULTI(TIS) was verified by analyzing the experimental data based on linear and nonlinear tank-in-series models. Linear one- and two-compartment tank-in-series models were adopted to analyze outflow time profiles in single-pass hepatic perfusion following a pulse input of 5'-deoxy-5-fluorouridine (DFUR). The estimated parameters agreed well with those by MULTI(FILT) which is widely used for linear kinetic analysis. The nonlinear models adopted were one-compartment model with Michaelis-Menten elimination and two-compartment models with Michaelis-Menten elimination from central and peripheral compartments. Oxacillin was used as a model drug, because time courses of oxacillin show a capacity-limited hepatic disposition following a pulse input in high doses to the liver (300, 1000, 3000 and 5000 microg). The hepatic recovery ratio (F(H)) of oxacillin increased with dose, whereas the mean transit time (tH) was almost constant. The maximum elimination rate constant (Vmax) and Michaelis constant (Km) of oxacillin were estimated to be 1980 microg/ml/min and 54.1 microg/ml, respectively. Thus, the reliability of MULTI(TIS) was demonstrated for the analysis of nonlinear local disposition, especially, capacity-limited elimination in the liver.

Functional assessment of liver for extended hepatic resection in patients with obstructive jaundice

We studied whether the maximal excretion rate of indocyanine green (ICG Bmax) and the 2-h ICG excretion rate in the bile could be used to estimate the separate functions of the left and right liver in 20 patients with biliary obstruction at the hepatic hilus. ICG Bmax was measured after biliary decompression. An operative procedure that preserved the side of the liver with a positive ICG Bmax value was selected. Eighteen patients tolerated extensive hepatic resection, such as right trisegmentectomy, extended right lobectomy, extended left lobectomy, or left lobectomy. However, prolonged jaundice was observed postoperatively in five of the six patients with 2-h excretion rates of less than 25% and who had undergone extended right lobectomy. One patient on whom extended right lobectomy had been performed died because of postoperative hepatic failure. His ICG Bmax value was +0.6 and his 2-h excretion rate was very low (3%). ICG Bmax and the 2-h excretion rate in the bile reflected well the degree of separate hepatic dysfunction in patients with biliary obstruction at the hepatic confluence. If ICG Bmax value is more than +1.0, resection of more than two segments, such as trisegmentectomy or extended hepatic lobectomy, may be tolerated, and if the ICG Bmax value is positive, hepatic lobectomy may be tolerated. ICG Bmax and 2-h excretion rate in bile are useful indicators of hepatic functional reserve of the separate lobes of the liver in patients with biliary obstruction at the hepatic hilus.

Phosphorus and ammonia excretion by planktonic protists

Excretion by grazers is an important source of the nutrients orthophosphate and ammonia to producers of organic particles (phytoplankton and bacteria). Excretion may be dominated by the smallest of particle consumers, planktonic protists, because metabolic rates per unit weight are usually inversely related to size. However, protist taxa are a heterogenous assemblage, ranging over 3 orders of magnitude in size, and include forms which are mixotrophic, profiting simultaneously from photosynthesis and ingestion of particulate matter. Excretion rates from laboratory studies of protists, ciliates and flagellates, both heterotrophic and mixotrophic, were analysed to determine relationships with both cell size and growth rate. Smaller protists, such as flagellates, showed higher weight-specific excretion rates than larger protists like ciliates. Equations relating maximal excretion rate (excr) to size in terms of dry weight (DW) were, for orthophosphate, log excr (μg P cell −1 h −1) = −2.101 +0.570 log size (mg DW cell −1), r = 0.847, n = 12 and for ammonia, log excr (μg N cell −1 h −1) = − 1.388 + 0.622 log mg DW cell −1, r = 0.899, n = 15. Mixotrophic protists showed maximum excretion rates similar to like-sized heterotrophic protists. For phosphorus, the maximum weight-specific excretion rates of protists were higher than predicted by extrapolation of most size-excretion rate relationships established for metazoan Zooplankton. Maximum excretion rates for ammonia approached the average of reported relationships for metazoan-based equations. Rapidly growing protozoa appear to excrete orthophosphate (measured as soluble reactive phosphorus) relative to ammonia well in excess of the Redfield atom ratio of 16:1 i.e., excretory N:P ratios of 2:1–8:1. For orthophosphate, excretion rate may be predictable based on cell size and growth rate. In contrast, ammonia excretion appeared weakly related to growth rate in five out of ten species, and independent of growth rate in the remaining species, probably due to variability of the form of nitrogenous excretion. Consequently, planktonic protists may be much more important in the regeneration of orthophosphate than ammonia. However, the apparent magnitude and simplicity of phosphorous excretion may be an artefact of considering the dominant excretory compound, soluble reactive phosphorus, as entirely orthophosphate.

Activités métaboliques et toxicité du dinoflagellé Alexandrium tamarense en culture à dialyse exposée à un milieu estuarien

Metabolic activities and toxicity of the dinoflagellate Alexandrium tamarense were studied for a dialysis culture exposed to unenriched natural seawater and a batch culture grown in an enriched medium. The following observations were made on the dialysis culture compared with the batch culture: (i) Depending on the season period, the cell densities per litre were similar (≈ 10 × 106 – 14 × 106) or greater (66 × 106). (ii) During growth and stationary phases, cellular consumption of the nutrients (NO3− + NO2−) was much greater (5–50 times), (iii) During growth, the composition of the intracellular (IFAA) and extracellular dissolved free amino acid (EFAA) was characterized by the presence of ORN and LYS in the dialysis culture, which represent a substantial fraction of the IFAA pool of the dinoflagellate; a significant depletion of the IFAA was observed, but the recovery of Gln, Glu, and Arg cell concentration levels at the stationary phase was more important. (iv) During the growth phase, the maximum excretion rate of amino acids (fmol∙cell−1∙d−1) was 263 (in decreasing order of importance: Glu, Gin, Ser, Asp, Leu, Ala, G+T, and Orn) compared with 14,5. (v) During stationary phase, the reduction in excretion activity was twofold with Gln, Glu, Leu, and Orn while 9,2 fmol∙cell−1∙d−1 were observed in batch culture, (vi) Total toxin content was about 4 to 5 times higher (means: 95 and 75 fmol∙cell−1 during growth and stationary phases respectively), with greater concentrations in more potent derivates like saxitoxin and neosaxitoxin. This higher cell toxicity may be attributed to the particular growth conditions of the dialysis culture, which more closely approximate the natural environment, through diffusion processes involving a constant elimination of low molecular weight autoinhibitory metabolites and a more efficient nutrient uptake.Key words: Alexandrium tamarense, dinoflagellate, dialysis culture, phycotoxins, nitrogen metabolism.

Pharmacokinetic and Pharmacodynamic Analysis Based on the Population Approach.

The population pharmacokinetic analysis is a relatively new approach, which can be used to obtain the pharmacokinetic and/or pharmacodynamic information required to make rational decision about the magnitude of an initial dose for a given patient, and of a subsequent dose if adjustment is needed. The present article reviews our recent effort for population pharmacokinetics, focusing on the analysis of phenytoin disposition. A simulation study was conducted to compare the performance of various models for population analysis of the steady-state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. It was indicated that the usual Michaelis-Menten model generally gives poor estimates of the maximal elimination rate and the Michaelis-Menten constant, and that the one-compartment model with dose-dependent clearance should be considered for estimating population pharmacokinetic parameters. The population pharmacokinetic parameters of phenytoin were estimated using 531 routine therapeutic drug monitoring data from 116 epileptic patients. In addition, we showed that the genetic polymorphism of CYP2C isoenzymes plays an important role in the pharmacokinetic variability of phenytoin. The population pharmacokinetic parameters of phenytoin and the genetic test for CYP2C isoenzymes will be useful in designing dosage regimens and/or in detecting patients at risk for the drug intoxication.

Excretion study of furazabol, an anabolic steroid, in human urine.

Furazabol and 16-hydroxyfurazabol represented the most abundant peaks in urinary metabolic profiles for two men obtained by gas chromatography-mass spectrometry (GC-MS) after oral administration of 5 mg furazabol. The excreted amounts of unchanged furazabol were determined and its response in GC-MS was compared with that of the 16-hydroxy metabolite. The maximum excretion rates of these compounds were reached 2-3 h after oral administration. The half-lives of unchanged furazabol for two human subjects, were 1.87 and 1.29 h respectively and the recovered amount in 48 h was 24% (33% for one, 15% for the other). Also the spectrum of an unidentified metabolite is reported.

Disposition of human drug preparations in the horse. V. Orally administered oxprenolol.

Urinary concentrations of the beta-antagonist oxprenolol and some of its major human metabolites were determined following oral administration of a dose of 160 mg to five fasted horses. Quantitation was performed by gas chromatography-mass spectrometry (GC-MS) in the selected ion mode (SIM) by monitoring ion m/z 466 of the heptafluorobutyric derivatives. As early as 2 h after dosage oxprenolol could be detected in hydrolysed urine and remained detectable up to 24 h. Maximum urinary concentrations and excretion rates were obtained between 2 and 12 h. After 12 h only 2.8% of the administered dose was excreted as conjugates of oxprenolol and major human metabolites including 4-OH-oxprenolol and 5-OH-oxprenolol. These metabolites were detectable up to 48 h.

Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.

The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients. Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM. The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found. Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.

Gas chromatography/mass spectrometry identification of long-term excreted metabolites of the anabolic steroid 4-chloro-1,2-dehydro-17α-methyltestosterone in humans

The misuse of anabolic steroids by athletes has been banned by sports organizations and is controlled by the analysis of urine samples obtained from athletes using gas chromatography/mass spectrometry (GC/MS). To extend the retrospectivity of the analytical methods, research is focused on long-term excreted metabolites. Preliminary results concerning the long-term detection of metabolites of the anabolic androgenic steroid 4-chloro-1,2-dehydro-17α-methyltestosterone I are presented. A new metabolite 4-chloro-3α,6β,17β-trihydroxy-17α-methyl-5β-androst-1-en-16-one II was isolated by high performance liquid chromatography (HPLC) from urine following a single oral administration of 40 mg of I and characterized. Metabolite II was excreted into urine with a maximum excretion rate at approximately 48 h after administration and could be detected by gas chromatography/high resolution mass spectrometry (GC/HRMS) for up to 14 days. Two further partly characterized metabolites III and IV were confirmed for more than 9 days. The same three metabolites, II-IV, in varying amounts were also detected in urine samples from athletes who administered I.

Effect of CYP2C polymorphisms on the pharmacokinetics of phenytoin in Japanese patients with epilepsy.

We examined the effect of CYP2C9/19 polymorphisms on the pharmacokinetics of phenytoin in 17 Japanese patients with epilepsy. The maximal elimination rate (Vmax) of phenytoin was slightly decreased (up to 14%) in patients with CYP2C19 mutations for the defective allele. The Vmax values in patients with a CYP2C9 mutation for the heterozygous Ile/Leu359 allele were 40% lower than those in patients with wild-type CYP2C9 for the homozygous Ile359 allele. These findings suggested that the genetic polymorphism of CYP2C isoenzymes plays an important role in the pharmacokinetic variability of phenytoin, and that the mutation in CYP2C9 proteins is a determinant of impaired metabolism of the drug.

Influence of phytogenic surfactants (quillaya saponin and soya lecithin) on bio-elimination of phenanthrene and fluoranthene by three bacteria

The influence of two phytogenic surfactants on the elimination of polycyclic aromatic hydrocarbons (PAH) was studied in shaken-batch cultures of three soil bacteria under axenic conditions. At sufficiently high concentrations, quillaya saponin and soybean lecithin solubilized phenanthrene or fluoranthene efficiently. However, complete solubilization of the PAH by lecithin only doubled the maximal rate of elimination of the two PAH compounds by Pseudomonas 0259, strain MKm (Rhizomonas ?) and Mycobacterium EMI 2. By contrast, quillaya saponin did not improve PAH bioavailability, and in strain MKm it caused significant growth lags above 2.5 g/l. Simultaneously with the elimination of the PAH the bacteria utilized the surfactants as substrates for growth. Intermediate formation of PAH metabolites was noted. The results suggest that some phytogenic surfactants might improve PAH bioavailability in rhizospheres.

Bioavailability and diuretic effect of furosemide following administration of tablets and retarded capsules to human subjects.

Two kinds of dosage forms (tablets and retarded capsules) of furosemide (F) were compared in vitro dissolution profile and in vivo absorption studies. The dissolution of F from retarded capsules was extremely restricted in the first fluid of the JP XII disintegration test (within 0.8%), while the dissolution of F from tablets and retarded capsules in the second fluid of JP XII disintegration test were both complete. Metabolite specific assay of F showed F, conjugation of F with glucuronic acid (FG) and acyl migration isomers of FG (FG-iso) in urine or plasma. The mean cumulative urinary excretion of F following administration of the tablets during 24 h was twice that of retarded capsules. The mean area under the plasma concentration-time curve (AUC) of F following administration of tablets was 1.5 times that of retarded capsules. The mean cumulative urine volume during 24 h, however, was not significantly different between the two dosage forms. Clockwise hysteresis relationships between the diuretic response and the urinary excretion rate of F was observed after administration of retarded capsules. A straight relation between logarithm of the diuresis and logarithm of the urinary excretion of F was observed after maximum excretion rate of F following administration of both dosage forms.

Nitrogenous excretion in juvenile turbot, Scophthalmus maximus (L.), under controlled conditions

Laboratory experiments on juvenile turbot. Scophthalmus maximus (L.), were carried out under controlled temperature (12°C) and feeding regimes in a flow-through system. Monitoring of total ammonia nitrogen (TAN) and urea nitrogen (Urea-N) was performed through continuous sampling of the effluent sea water. The effects of ingested nitrogen levels on TAN and Urea-N daily and hourly excretion rates were studied. Strong relationships were found between ingested nitrogen, and both TAN and Urea-N excretion for both daily and hourly maximum excretion rates. Turbot showed a low metabolic activity, confirmed by low excretion levels. Daily patterns for TAN and Urea-N production were different, suggesting specific physiological phenomenon for urea excretion mechanisms. The question of whether turbot are partly ureotelic or ureogenic is underlined.

Disposition of human drug preparations in the horse IV. Orally administered fenoprofen

Plasma and urinary concentrations of the non-steroidal anti-inflammatory drug fenoprofen were determined by a high-performance liquid chromatographic procedure following oral administration of a dose of 3 g to fed and fasted horses. In plasma, fenoprofen was present in detectable concentrations for 6–12 h. Free access to hay significantly reduced the peak plasma concentration and bioavailability of fenoprofen, and large interindividual differences in absorption and elimination pattern occurred. In fasted horses, fenoprofen was rapidly absorbed with a mean half-life of 0.10 h. Maximum concentrations were found 0.63 ± 0.21 h after dosing. The elimination half-life was 0.9 h. As early as 1 h after dosage, fenoprofen could be detected in hydrolysed and unhydrolysed urine, and remained detectable up to 48 h. The maximum excretion rate and peak concentration occurred 2 h after administration, irrespective of the feeding schedule. In fed horses, a second maximum occured after 9 h. The percentage of the dose excreted as unchanged fenoprofen in 12 h was 13.0 ± 6.8%. A recovery of 21.9 ± 7.4%, and 42.2 ± 7.0% of the dose was obtained after enzymatic and alkaline hydrolysis, respectively. At least three hydroxylated metabolites were detected in hydrolysed urine.

Comparative Toxicokinetics of Methanol in the Female Mouse and Rat

Comparative Toxicokinetics of Methanol in the Female Mouse and Rat. Ward, K. W., Perkins, R. A., Kawagoe, J. L., and Pollack, G. M. (1995). Fundam. Appl. Toxicol. 26, 258-264. The toxicokinetics of methanol in female CD-1 mice and Sprague-Dawley rats were examined to explore the possibility of species differences in the disposition of the compound. Mice received a single dose of 2.5 g/kg methanol either po (by gavage) or iv (as a 1-min infusion). Rats received a single oral dose of 2.5 g/kg methanol. As expected, the disposition of methanol was nonlinear in both species. Data obtained after iv administration of methanol to mice were well described by a one-compartment model with Michaelis-Menten elimination. Blood methanol concentration-time data after oral administration could be described by a one-compartment (mice) or two-compartment (rats) model with Michaelis-Menten elimination from the central compartment and biphasic absorption from the gastrointestinal tract. Kinetic parameters ( V max for elimination, apparent volume of the central compartment [ V c], first-order rate constants for intercompartmental transfer [ k 12 and k 21], and first-order absorption rate constants for fast [ k AF] and slow [ k AS] absorption processes) were compared between species. When normalized for body weight, mice evidenced a higher maximal elimination rate than rats ( V max = 117 ± 3 mg/hr/kg vs 60.7 ± 1.4 mg/hr/kg for rats). The contribution of the fast absorption process to overall methanol absorption also was larger in the mouse than in the rat.

Use of oral and intravenous fat tolerance tests to assess plasma chylomicron clearance in dogs

The reduced clearance of chylomicrons from plasma results in an exaggerated post prandial lipaemia and fasting hypertriglyceridaemia. This study evaluated whether oral and intravenous fat tolerance tests are appropriate for the in vivo analysis of chylomicron clearance in dogs. Plasma and chylomicron triglyceride concentrations were measured in eight beagles after the administration of a cream-based meal of 2·35 g fat kg −l bodyweight. The changes in each parameter were determined chiefly by the activity of lipoprotein lipase, which was measured in plasma collected after the intravenous injection of heparin and did not appear to be influenced by intestinal fat absorption. The inclusion of retinyl palmitate in the meal provided additional information on the metabolic fate of chylomicron remnants. After the intravenous injection of 0·1 g Intralipid kg −1 bodyweight, there was an initial linear decay in plasma triglyceride concentrations that represented the maximal elimination rate K 1. This was followed by a second exponential component so that the plasma triglyceride concentration returned to baseline by 60 minutes. Lipoprotein lipase was the major determinant of K 1 and the area under the curve of plasma triglycerides.