Biomedical subjects

J Gabrielsson

Publications and source records attributed to J Gabrielsson.

At least 19 recordsLinked to original sources

PubMed2001

Neuroprotective efficacy of AR-A008055, a clomethiazole analogue, in a global model of acute ischaemic stroke and its effect on ischaemia-induced glutamate and GABA efflux in vitro.

We have investigated the neuroprotective properties of AR-A008055 [(+/-)-1-(4-methyl-5-thiazolyl-1-phenyl-methylamine], a novel compound structurally related to clomethiazole. Administration (i.p.) of (+/-)-AR-A008055 60 min after 5 min of global cerebral ischaemia in gerbils produced a dose-dependent protection of the hippocampus from damage. Both enantiomers [(R)-(+)-AR-A008055 and (S)-(-)- AR-A008055] at 600 micromol/kg produced similar protection to that following clomethiazole (600& micromol/kg) and both produced similar and sustained neuroprotection, at 4, 7 and 21 days post-insult. When infused intravenously over a 2-h period, both enantiomers produced concentration-dependent neuroprotection, with the enantiomers providing similar protection at every plasma concentration (50-200 nmol/ml). The efficacy of (S)-(-)-AR-A008055 was similar to clomethiazole, but it was slightly less potent. Ischaemia-induced glutamate efflux from rat brain cortical prisms in vitro was inhibited by both isomers (100 microM). The inhibitory effect of (R)-(+)-AR-A008055 was blocked by bicuculline (10 microM) and picrotoxin (100 microM), while the effect of (S)-(-)-AR-A008055 was only antagonised by picrotoxin. This indicated that (S)-(-)-AR-A008055, like clomethiazole, is able to open the GABA(A)-chloride channel in the absence of endogenous GABA. (R)-(+)-AR-A008055 was more potent than (S)-(-)-AR-A008055 in enhancing the concentration of GABA in the medium following 30 min exposure of tissue to the ischaemic conditions, suggesting that it is an effective GABA uptake inhibitor. This action may explain both its effect on glutamate efflux in vitro and its neuroprotective effect in vivo.

Animals↗

PubMed2001

Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man.

H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irreversible proton pump inhibitors (PPIs) is better control over the effect-time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs (n=24) and healthy male subjects (n=12). The effect-time profile was delayed compared to the concentration-time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug-enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug-enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models 1 and 3, for both dog and human data. The dissociation rate constant, k(off), was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K(d), was 160 and 250 nM in dog and man, respectively. Simulations of the predicted time-course of the effect beyond the 4-5-h observation period was similar for the three models.

Administration, Oral↗

PubMed2001

Do ethanol and deuterium oxide distribute into the same water space in healthy volunteers?

BACKGROUND: The volume of distribution at steady state for ethanol (Vss) is thought to be identical to the total body water (TBW). We compared a two-compartment pharmacokinetic model with parallel Michaelis-Menten and first-order renal elimination with the classical one-compartment zero-order elimination model. Ethanol concentration-time profiles were established for breath, venous blood, and urine. The values of Vss obtained for ethanol were compared with TBW determined by deuterium oxide dilution. METHODS: Sixteen healthy volunteers each received a 30-min intravenous infusion of ethanol on two occasions. Ethanol was measured in breath by a quantitative infrared analyzer and in blood and urine by headspace gas chromatography. Deuterium oxide was given as an intravenous injection and measured in serum by isotope-ratio mass spectrometry. Components of variation were calculated by ANOVA to determine the precision of the estimates of Vss and TBW. RESULTS: Mean TBW, determined by deuterium oxide dilution, was 44.1 +/- 3.9 liters (+/-SD) for men, corresponding to 0.61 liters/kg, and 37.4 +/- 3.2 liters for women, or 0.54 liters/kg. Estimates of Vss from blood-ethanol pharmacokinetics were 87.6% of TBW according to isotope dilution and 84.4% for breath analysis with the two-compartment model. This compares with 95.1% and 95.4% for blood and breath alcohol, respectively, when the classical zero-order kinetic analysis is used. The precision of the estimates of Vss and TBW was between +/-1.56 and +/-2.19 liters (95% confidence interval). CONCLUSIONS: Ethanol does not distribute uniformly into the TBW. The precision of measuring Vss by ethanol dilution was comparable to estimates of TBW by isotope dilution. Results of noninvasive breath ethanol analysis compared well with use of venous blood for estimating Vss. The sophisticated two-compartment model was much superior to the classical one-compartment model in explaining the total concentration-time course of intravenously given ethanol.

Adult↗

PubMed2000

Modeling of dose-response-time data: four examples of estimating the turnover parameters and generating kinetic functions from response profiles.

The most common approach to in vivo pharmacokinetic and pharmacodynamic modeling involves sequential analysis of the plasma concentration versus time and then response versus time data, such that the plasma kinetic model provides an independent function, driving the dynamics. However, response versus time data, even in the absence of measured drug concentrations, inherently contain useful information about the turnover characteristics of response (turnover rate, half-life of response), the drug's biophase kinetics (F, half-life) as well as the pharmacodynamic characteristics (potency, intrinsic activity). Previous analyses have assumed linear kinetics, linear dynamics, no time lag between kinetics and dynamics (single-valued response), and time constant parameters. However, this report demonstrates that the drug effect can be indirect (antinociception, cortisol/adrenocorticotropin (ACTH), body temperature), display nonlinear kinetics, display feedback mechanisms (nonstationarity, cortiso/ACTH) and exhibit hysteresis with the drug levels in the biophase (antinociception, body temperature). It is also demonstrated that crucial determinants of the success of modeling dose-response-time data are the dose selection, multiple dosing, and to some extent different input rates and routes. This report exemplifies the possibility of assigning kinetic forcing functions in pharmacodynamic modeling in both preclinical and clinical studies for the purpose of characterizing (discrimination between turnover and drug-specific parameters) response data and optimizing subsequent clinical protocols, and for identification of inter-individual differences.

Animals↗

PubMed2000

Within- and between-subject variations in pharmacokinetic parameters of ethanol by analysis of breath, venous blood and urine.

AIMS: To evaluate the prerequisites for using ethanol dilution to estimate total body water, we studied the within- and between-subject variation in the parameter estimates of a two-compartment model for ethanol pharmacokinetics with parallel Michaelis-Menten and first-order renal elimination. Because sampling of breath might be preferable in some clinical situations the parameter estimates derived from breath and venous blood were compared. METHODS: On two occasions, ethanol 0.4 g kg-1 was given by intravenous infusion to 16 volunteers after they had fasted overnight. The proposed model was fitted by means of nonlinear regression to concentration-time data measured in the breath, venous blood and urine during 360 min. The model contained six parameters: Vmax and Km (Michaelis-Menten elimination constants), CLd (intercompartmental distribution parameter), VC and VT (volumes of the central and tissue compartment, respectively) and CLR (renal clearance). The volume of distribution, Vss, was calculated as the sum of VC and VT. RESULTS: The mean +/- total s.d. of the parameter estimates derived from blood data were Vmax 95 +/- 25 mg min-1, Km 27 +/- 19 mg l-1, CLd 809 +/- 232 ml min-1, VC 14.5 +/- 4.3 l, VT 21. 2 +/- 4.4 l, CLR 3.6 +/- 2.0 ml min-1 and Vss 35.8 +/- 4.3 l. The variation within subjects amounted to 3%, 9%, 21%, 21%, 17%, 26% and 2%, respectively, of the total variation. Breath samples were associated with a similar or lower variation than blood, both within and between subjects. About 1.5% of the infused ethanol was recovered in the urine. CONCLUSIONS: The low within-subject variation of the key parameter Vss (only 2%) suggests that ethanol dilution analysed by the pharmacokinetic model applied here may be used as an index of the total body water. Breath samples yielded at least as good reproducibility in the model parameters as venous blood.

Adult↗

PubMed2000

Multivariate methods in developing an evolutionary strategy for tablet formulation.

The aim of this study was to develop a new strategy for choosing excipients in tablet formulation. Multivariate techniques such as principal component analysis (PCA) and experimental design were combined in a multivariate design for screening experiments. Of a total 87 investigated excipients, the initial screening experiments contained 5 lubricants, 9 binders, and 5 disintegrants, and 35 experiments were carried out. Considering a reduced factorial design was used, the resulting PCA and partial least squares (PLS) models offered good insight into the possibilities of tablet formulation. It also offered solutions to the problems and clearly gave directions for optimum formulations. Further, it offered several alternatives for achieving quality formulations. Additional experiments conducted to validate and verify the usefulness of the model were successful, resulting in several tablets of good quality. The conclusion is that a multivariate strategy in tablet of formulation is efficient and can be used to reduce the number of experiments drastically. Combining multivariate characterization, physicochemical properties, experimental design, multivariate design, and PLS would lead to an evolutionary strategy for tablet formulation. Since it includes a learning strategy that continuously incorporates data for new compounds and from conducted experiments, this would be an even more powerful tool than expert systems.

Chemistry, Pharmaceutical↗

PubMed2000

A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog.

A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short-term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, which inhibited the acid secretion for several days. Combining the short-term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order association rate constants (k(ome)) for the covalent binding of omeprazole to H(+),K(+)-ATPase were estimated to 11 and 3.0 l/micromol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k(out) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model.

Animals↗

PubMed1998

Time course of enzyme induction in humans: effect of pentobarbital on nortriptyline metabolism.

To study the effect of induction we gave six male volunteers 10 mg nortriptyline three times a day for 4 weeks and 0.2 gm pentobarbital on days 8 to 21. Plasma and urinary levels of nortriptyline and metabolites were measured. The rate and extent of induction of the enzyme(s) were estimated by a model with use of nortriptyline concentrations. There was a marked decrease of nortriptyline levels after 2 days of pentobarbital treatment. Total clearance of nortriptyline increased more than twofold (range, 1.6-fold to 4.1-fold). Apparent metabolic clearance by 10-hydroxylation increased markedly. The decrease in nortriptyline levels was more rapid than the increase after pentobarbital cessation, fitting with the theory of the model. The induction of nortriptyline metabolism is probably mainly the result of an increase in a non-CYP 2D6 P450 isozyme, possibly CYP 3A4 or a CYP 2C form. More knowledge of induction characteristics of drugs should lead to better predictions of decreased effects and appearance of adverse effects. The kinetic model used for analysis of our data could then be useful.

Adrenergic Uptake Inhibitors↗

PubMed1998

Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine.

OBJECTIVE: To determine whether cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamic (heart rate, accommodation, and salivation) of tolterodine and its 5-hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin (INN, debrisoquine). METHODS: Sixteen male subjects (eight extensive metabolizers and eight poor metabolizers) received 4 mg tolterodine by mouth twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period. Doses were given as the tartrate salt. The pharmacokinetics of tolterodine and 5-hydroxymethyl metabolite were determined, and the pharmacodynamic were measured. RESULTS: The mean systemic clearance of tolterodine was significantly lower (p < 0.001) among poor metabolizers (9.0 +/- 2.1 l/hr) compared with extensive metabolizers (44 +/- 13 L/hr), resulting in a fourfold longer elimination half-life (p < 0.001). The terminal half-life of the 5-hydroxymethyl metabolite (2.9 +/- 0.4 hours) was slightly longer than that of the parent compound (2.3 +/- 0.6 hours) among extensive metabolizers, but the 5-hydroxymethyl metabolite was undetectable in the serum of poor metabolizers. Only minor differences in pharmacodynamic effects after tolterodine dosage were observed between the groups. Tolterodine caused a similar decrease in salivation in both panels. The decrease occurred when the concentration of unbound tolterodine and 5-hydroxymethyl metabolite among extensive metabolizers was comparable with that of tolterodine among poor metabolizers. CONCLUSIONS: Tolterodine is extensively metabolized by CYP2D6 with high specificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite.

Administration, Oral↗

PubMed1998

The influence of drug input rate on the development of tolerance to frusemide.

AIMS: Understanding the impact of drug input rate on its pharmacokinetic-pharmacodynamic relationship may lead to a more optimal drug therapy. The aim of the present study was to investigate the influence of the rate of administration on tolerance development to frusemide, by giving the drug at four different infusion rates. METHODS: Eight healthy volunteers were given 10 mg of frusemide on four different occasions, as a constant-rate intravenous infusion during 10, 30, 100 and 300 min, respectively. Urinary volume and contents of frusemide and sodium were measured in samples collected over 8 h. RESULTS: The four different infusion rates systematically influenced the frusemide excretion rate versus diuretic and natriuretic response relationship. Counter-clockwise hysteresis occurred for the most rapid infusion rate, whereas a progressive clockwise hysteresis was observed for the slower infusions, indicating development of tolerance. For each subject, diuresis and natriuresis were modeled for all four treatments simultaneously, using a feedback tolerance model. It was not possible to describe the data using a model without tolerance. The time course of tolerance development showed remarkable differences between the infusion rates. The intensity of maximum tolerance development was significantly less for the slowest infusion rate compared with the more rapid infusions and it appeared significantly later. However, no differences in diuretic or natriuretic response were found between the treatments. CONCLUSIONS: The direction of the hysteresis loop is dependent on the input rate of frusemide. After the administration of a single low dose of frusemide, the time course of tolerance, rather than the integrated time course of tolerance, is influenced by the drug input rate.

Adult↗

PubMed1997

Pharmacokinetics and pharmacodynamics of tolterodine in man: a new drug for the treatment of urinary bladder overactivity.

The aim of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of tolterodine following single oral and intravenous doses in healthy volunteers. A secondary aim was to identify major urinary metabolites and determine mass balance. Single oral doses of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg of tolterodine (as the tartrate salt) were given to 17 healthy male volunteers. Two intravenous doses (0.64 and 1.28 mg) were administered to 8 of the volunteers and mass balance was studied after a single oral dose of 5 mg (14C)-tolterodine in 6 subjects. Tolterodine was rapidly absorbed following oral administration (time to peak serum concentration 0.9 +/- 0.4 h). The absolute bioavailability was highly variable, ranging from 10 to 70%. The volume of distribution at steady-state ranged from 0.9 to 1.6 l/kg and systemic clearance ranged from 0.23 to 0.52 l/h/kg, which resulted in a terminal half-life of 2-3 h. Tolterodine exhibited high first-pass metabolism and 2 hepatic metabolic pathways were identified: oxidation and dealkylation. Independent of route of administration, < 1% of the parent compound was excreted unchanged in urine. Five metabolites were structurally identified in urine. Following oral administration of (14C)-tolterodine, the excretion of radioactivity into urine and feces was 77 +/- 4.0% and 17 +/- 3.5%, respectively. Tolterodine decreased stimulated salivation after 3.2 mg, increased heart rate after 6.4 mg, and nearpoint of vision after 12.8 mg. Six of 8 subjects reported micturition difficulties after a dose of 12.8 mg. The lack of a direct relationship between tolterodine serum concentrations and effects on stimulated salivation suggested the presence of pharmacologically active metabolite(s).

Adult↗

PubMed1996

Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration.

OBJECTIVE: Physiologic indirect-response models have been proposed to account for the pharmacodynamics of drugs with an indirect mechanism of action, such as furosemide. However, they have not been applied to tolerance development. The aim of this study was to investigate the development of tolerance after multiple intravenous dosing of furosemide in healthy volunteers. METHODS: Three repetitive doses of 30 mg furosemide were given as rapid intravenous infusions at 0, 4, and 8 hours to eight healthy volunteers. Urine samples were collected for a period up to 14 hours after the first dose. Volume and sodium losses were isovolumetrically replaced with an oral rehydration fluid. RESULTS: Tolerance was demonstrated as a significant decrease in diuretic and natriuretic response over time. Total mean diuresis was 35% lower (p < 0.01) and total mean natriuresis was 52% lower (p < 0.0001) after the third dose of furosemide compared with the first dose. However, there were considerable interindividual variations in the rate and extent of tolerance development for both diuresis and natriuresis. Pharmacokinetic-pharmacodynamic modeling of tolerance development was performed with use of an indirect-response model with an additional "modifier" compartment. This model gave an accurate description of the diuretic and natriuretic data after multiple dosing of furosemide and enabled the estimation of a lag-time for tolerance and a rate constant for tolerance development. Physiologic counteraction was demonstrated as a significant increase in plasma active renin levels (p < 0.00001) and a decrease in atrial natriuretic peptide levels (p < 0.005) during the day, concomitantly with the development of a negative sodium balance. This may be viewed as physiologic reflections of the modifier in our model. CONCLUSION: Indirect-response models may be successfully applied for tolerance modeling of drugs after multiple dosing.

Adult↗

PubMed1996

Pharmacokinetic data on estradiol in light of the estring concept. Estradiol and estring pharmacokinetics.

The pharmacokinetics and pharmacodynamics of estradiol in humans are briefly reviewed in this paper. The estradiol vaginal ring was designed and developed to obtain controlled local delivery of very low doses of estradiol resulting in a marginal effect on plasma concentrations of estradiol, associated with a margin of safety over a prolonged period of time. Three clinical studies in postmenopausal women with signs and symptoms while plasma levels remain virtually unchanged in the lower part of the normal postmenopausal range. No pharmacodynamic effects of estrogen could be detected, reflecting a very low systemic exposure. The estradiol exposure and the plasma concentration time course during treatment with first and second ring during first month of the intended three month treatment period are compared. The very low systemic exposure is discussed in relation to existing therapies. Ongoing pharmacokinetic work with estradiol vaginal ring is briefly described. It is concluded that the estradiol vaginal ring is a very stable alternative to existing vaginal therapies, resulting in a very low systemic exposure to estradiol, and is associated with a minimal risk of drug interaction and has a high margin of safety.

Administration, Topical↗

PubMed1995

New kinetic data on estradiol in light of the vaginal ring concept.

The principal estrogen produced by the functioning premenopausal ovary is 17 beta-estradiol. At the point of irreversible ovarian failure, at menopause, the production of estradiol decreases dramatically, which results in circulating serum levels less than 120 pmol/l. It is important to recognise the pharmacokinetic and metabolic outcomes associated with dosage and route of delivery of estrogen. One of the most promising methods of administering estrogen replacement therapy (ERT) for local effects is the estradiol vaginal ring designed for a controlled continuous low release (7.5 micrograms estradiol/24 h) over a period of 90 days. The present study was undertaken to characterise the basal endogenous turnover of estradiol in postmenopausal women. Information on the disposition of estradiol after an intravenous dose formed the base of the kinetic model. The rate of extent of absorption of estradiol was assessed after ring application. Individual serum concentrations of estradiol were analysed without subtraction of the basal estradiol levels. The results indicate a rapidly eliminated compound (plasma clearance 2 l/min) with a distribution of approximately 50 l, resulting in an efficient half-life of about 20 min. The endogenous production was highly variable (< 1-44 micrograms/24 h). The steady-state estradiol levels following ring application did not increase and were well within the normal basal estradiol range seen in untreated women. In light of the present findings, the low daily dose, the low availability of estradiol across the vaginal wall and the controlled local delivery, favour the use of the estradiol vaginal ring.

Administration, Intravaginal↗

PubMed1995

Concomitant single-dose and multiple-dose pharmacokinetics of terodiline in man, with a note on its enantiomers and major metabolites.

Single-dose and multiple-dose pharmacokinetics of terodiline were studied in 20 healthy volunteers by giving an initial oral dose of deuterium-labelled terodiline (12.5 mg or 25 mg) followed by multiple doses of Mictrol tablets (12.5 mg b.i.d. for 14 days and 25 mg b.i.d. for 14 days or vice versa). The enantiomer serum concentration ratio of S(-)/R(+) terodiline was close to unity at steady-state as well as during the disposition phase. The average single-dose kinetic parameters for the racemate after the 12.5 mg dose were: maximum serum concentration 41 micrograms/l, the corresponding time 3.4 hr, terminal half-life 61 hr, oral clearance 77 ml/min., renal clearance 12 ml/min. and apparent volume of distribution 382 1. The single-dose kinetics for the 25 mg dose and the multiple-dose kinetic parameters showed that linear kinetics prevailed. The average steady-state serum concentration was 275 micrograms/l at the lower dose and 509 micrograms/l at the higher dose. The degree of fluctuation during a dosage interval was 19% and the time to steady-state was about 9 days. The fraction unbound was about 8%. Unconjugated p-hydroxylated terodiline, p-hydroxy-m-methoxyterodiline and hydroxy-tert-butyl-terodiline constituted 15%, < 1% and 5%, respectively, of the terodiline steady-state levels.

Adult↗

PubMed1994

Kinetics of circulating hyaluronan in humans. 4.

The elimination of intravenously injected hyaluronan (HA) from the blood was investigated in 12 healthy volunteers. Three consecutive 30 min infusions of HA were given, separated by 90 min washout periods. Blood samples were taken before, during and after each infusion and the plasma HA concentration was determined. The deposition of HA was modelled according to a Michaelis-Menten kinetic model which included natural synthesis of HA. Km and Vmax was estimated to 0.34 +/- 0.13 microgram ml-1 and 3.48 +/- 0.97 microgram min-1 kg-1 b.w., respectively. The endogenous input was calculated to be 24 +/- 11 micrograms min-1 and was found to correlate to the age of the subjects (P < 0.05). As the baseline HA concentration was 0.031 +/- 0.21 microgram ml-1, the rate of elimination was linear in the normal concentration range. The calculated Vd was about 75% higher than a weight-estimated plasma volume. The total amount of HA excreted by the kidneys during the study period was 394 +/- 77 micrograms, which corresponded to approximately 1.7% of the total input of HA into the circulation during the experiment.

Adult↗

PubMed1994

Eating a meal increases the clearance of ethanol given by intravenous infusion.

We studied the effect of eating a meal on the rate of ethanol elimination (clearance) from the blood after giving 0.4 g/kg by intravenous infusion to six female and six male volunteers. Half of the subjects had eaten breakfast whereas the other half had fasted overnight. After the first infusion of alcohol, those who had fasted ate lunch, and all the volunteers received a second infusion with the same dose of ethanol. The blood ethanol concentration was measured repeatedly for up to 180-240 min after the start of each experiment. Intake of food (lunch or breakfast) increased the clearance of ethanol by about 60% (P < 0.001). Alcohol intoxication was less pronounced at the end of the ethanol infusions preceded by eating a meal (P < 0.01). Gender had no significant effect on the rate of ethanol elimination. We conclude that eating a meal increases the rate of ethanol elimination even when alcohol is given by intravenous infusion.

Adult↗

PubMed1993

Non-steady-state kinetics of low density lipoproteins in man: studies after plasma exchange in healthy subjects and patients with familial hypercholesterolaemia.

Five patients with heterozygous familial hypercholesterolaemia (FH), one patient with non-familial hypercholesterolaemia, and four healthy normals were treated with plasma exchange (PE). In order to achieve a non-steady-state situation with low plasma cholesterol levels, PE was performed twice in each subject at an interval of 1-3 days. At each time, 1500 ml of plasma were removed and replaced with colloids and albumin. Lipoprotein analyses were performed daily in all subjects for a period of 14 days following PE. Kinetic calculation of LDL cholesterol data using a two-compartment open model was performed, and rate constants, synthetic rate and apparent clearance of LDL were determined. A lower clearance and a tendency towards a higher synthesis of LDL were observed in the FH patients. In four of the subjects, LDL kinetics was also studied with the conventional 125I-LDL turnover technique. The synthetic rates of LDL were compared using data derived from PE and 125I-LDL kinetics. The two techniques showed a good correlation (r = +0.93) although synthetic rates in general were higher when calculated from the 125I-LDL procedure (3.98 vs. 2.64 mmol d-1 for LDL cholesterol synthesis). The results indicate that non-steady-state kinetics of LDL, as measured using the PE technique, is a useful method for analysis of LDL metabolism.

Adult↗