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PubMed1986

Oral absorption of 21-corticosteroid esters: a function of aqueous stability and intestinal enzyme activity and distribution.

The intestinal absorption of hydrocortisone and prednisolone are compared with three water-soluble derivatives (succinate, phosphate, and lysinate) in experiments at two levels of biological system complexity. Rates of absorption are compared by measuring permeabilities from rat intestinal perfusions of drugs and derivatives in solution. Extents of absorption are compared over a 10-fold dose range of parent steroid and with the steroid derivatives by measuring plasma levels from solid oral dosage in dogs. While the parent steroids are well absorbed over the entire length of the intestinal tract, variability in plasma levels is observed at higher doses. Limited solubility and resultant dissolution rate variability are likely to be playing a role in the early erratic blood level profiles found at higher doses. While the soluble prodrugs have a dissolution rate advantage which results in a greater concentration gradient, their absorption is limited by their aqueous luminal stability, their polarity and resultant passive membrane permeability, and the distribution and activity of enzyme reconversion sites in the intestinal tract. The unstable lysinate ester, targeted for aminopeptidase, has an absorption profile and permeability similar to that of the parent steroid. The absorption of the moderately stable succinate ester is limited by its polarity and the activity of intestinal esterases. The stable phosphate derivative is well absorbed in the upper intestine, where high levels of alkaline phosphatase exist, while the prodrug polarity and drop-off of enzyme activity limit its absorption from the lower gastrointestinal (GI) tract.

Adrenal Cortex Hormones↗
PubMed1988

Intragastric behavior and absorption kinetics of a normal and "floating" modified-release capsule of isradipine under fasted and fed conditions.

From measurements of drug levels in both gastric juice and plasma, we investigated whether or not a prolonged gastric residence time (GRT) is responsible for the slow absorption kinetics of a "floating" modified-release (MR) capsule of isradipine [isopropyl methyl (+/-)-4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate], a lipophilic dihydropyridine calcium channel blocker. The effects of a "high-fat" breakfast on the intragastric behavior and absorption kinetics were also assessed. In an open crossover design, five healthy subjects ingested either a normal or MR capsule of isradipine under fasted conditions. Serial samples of gastric juice (obtained via an indwelling nasogastric tube) and plasma were collected up to 24 h after drug intake, and were analyzed for isradipine by GC and RIA methods, respectively. The pH and titratable acid, protein, and pepsin concentrations of the gastric juice samples were also determined. Four additional subjects were similarly studied after ingesting the capsules following a high-fat breakfast. Under fasted conditions, gastric juice drug levels of the normal and MR capsules indicated a median GRT of less than 1.5 h in both cases. Plasma levels indicated a rapid absorption for the normal capsule (less than 2 h), but a remarkably slow absorption for the MR capsule, lasting 24 h or more. Under fed conditions, gastric juice and plasma profiles of the normal capsule were similar to those for the fasted case. In contrast, the MR capsule had an increased GRT (approximately 2.4 to 4.8 h) that was associated with a delayed and more extensive intragastric drug release. The corresponding plasma profiles showed a rapid absorption phase which correlated closely with the intragastric release kinetics. The influence of a high-fat meal on the release kinetics of the MR capsule did not appear related to the intragastric pH, or acid, protein, or pepsin concentrations. From these results we conclude that: (1) a prolonged GRT is not responsible for the slow absorption achieved with a "floating" MR capsule; (2) the presence or absence of food, rather than buoyancy, is the principal determinant of the GRT of the MR capsule; (3) the release and absorption of a lipophilic drug from a "floating" MR capsule may be affected by intragastric interaction with the lipid phase of meal; and (4) the major portion of drug release from the MR capsule takes place in the colon, rather than in the stomach.

Adult↗
PubMed1988

Systemic absorption of ocularly administered enkephalinamide and inulin in the albino rabbit: extent, pathways, and vehicle effects.

The systemic absorption of ocularly applied tritiated [D-Ala2]metenkephalinamide (YAGFM) and inulin was studied in the albino rabbit with respect to rate, extent, pathways, and vehicle effects and compared with epinephrine. Peak concentration was achieved within 20 min except for inulin, for which absorption was still ongoing at 120 min. For YAGFM, the apparent absorption rate was slower than the elimination rate, thus obeying "flip-flop" pharmacokinetics. Based on the area under the plasma concentration curve from zero to 120 min, the percent of dose systemically absorbed was 36.1 +/- 4.4% for YAGFM, at least 3.3 +/- 0.2% for inulin, and 58.5 +/- 4.4% for epinephrine. This suggests that loss of drug to the systemic circulation is a more important factor in reducing the ocular absorption of YAGFM than for inulin. The conjunctival mucosa played as important a role as the nasal mucosa in the systemic absorption of YAGFM, while playing a secondary role in the case of inulin. Unlike nonpeptide drugs, the systemic absorption of ocularly administered YAGFM and inulin was not adversely affected by incorporation in 5% polyvinyl alcohol. Overall, the contact time of the instilled dose with the conjunctival and the nasal mucosae, their intrinsic permeability, and the extent of dilution of the instilled dose are key factors determining the vehicle effects on the extent of systemic absorption of ocularly applied peptides.

Administration, Intranasal↗
PubMed2004

Using a non-invasive stable isotope tracer to measure the absorption of water in humans.

The development of solutions that prevent dehydration or promote adequate re-hydration play a vital role in preventing fatigue during exercise, however, the methods commonly used to assess the hydration ability of such solutions are invasive and often assess the components of absorption separately. This paper describes using a non-invasive deuterium tracer technique that assesses gastric emptying and intestinal absorption simultaneously to evaluate the uptake of water during rest and exercise. The kinetics of absorption are further examined by mathematical modelling of the data generated. For the rest group, 0.05 g/kg of body weight of deuterium, contained in gelatine capsules, was ingested with ordinary tap water and saliva samples were collected every 5 min for one hour while the subject remained seated. The deuterium was administered as above for the exercise group but sample collection was during one hour of exercise on a treadmill at 55% of the subject's maximum heart rate. The enrichment data for each subject were mathematically modelled and the parameters obtained were compared across groups using an independent samples t-test. Compared with the rest condition, the exercise group showed delayed absorption of water as indicated by significant differences for the modelling parameters t2, t1/2, maximum absorption rate and solution absorption amount at t1. Labelling with a deuterium tracer is a good measure of the relative rate ingested fluids are absorbed by the body. Mathematical modelling of the data generates rates of maximum absorption and allows calculation of the percentage of the solution that is absorbed at any given time during the testing period.

Adolescent↗
PubMed2001

Mineral status of female rats affects the absorption and organ distribution of dietary cadmium derived from edible sunflower kernels (Helianthus annuus L.).

The intake of food cadmium (Cd) in microg/day over time can increase the body burden of this element. Some human populations that consume subsistence rice-based diets low in calcium (Ca), iron (Fe), and zinc (Zn) are more susceptible to Cd poisoning than populations that consume more nutritious diets. This study determined the effects of marginal deficiencies of these essential elements on the absorption and organ retention of Cd from a natural food that contains Cd, edible sunflower kernels (Helianthus annuus L.; SFK). Weanling female rats were fed diets containing 20% SFK in a 2x2x2 factorial design with marginal and adequate amounts of Ca, Zn, and Fe. Marginal Zn (11 mg/kg) and Fe (13 mg/kg), and Cd (0.18 mg/kg) were derived solely from 20% SFK. These amounts of Fe and Zn represented 39 and 90% of the NRC requirement for the rat, respectively. The marginal dietary Ca concentration (2.5 g/kg) was one-half the NRC requirement. After 5 weeks on the experiment, rats were fed 1 g of their respective diets containing SFK extrinsically labeled with 37 kBq 109Cd, and absorption was determined by whole-body counting techniques. Rats were then killed and organs collected for 109Cd assays. No effect of treatment on weight gain was observed; however, when dietary Zn was low, feeding marginal Ca elevated Cd absorption by 50% (P<0.05) over those fed adequate Ca and Zn. Feeding marginal Fe elevated Cd absorption >2.5-fold (P<0.001) over those fed adequate Fe. In contrast, the naturally occurring Zn in SFK that provided 90% of the rat's requirement was enough to deter excessive absorption of Cd and enough to alone prevent significant elevation of organ Cd. Organ content of 109Cd and Cd followed the same general pattern as whole-body absorption. These data show that marginal nutritional deficiencies of Ca and Fe can readily enhance the body burden of Cd that comes from the diet. Also, some natural competitors of Cd, such as Zn, contained in foods can independently minimize Cd absorption.

Absorption↗
PubMed1997

Absorption lineshapes in two-dimensional electron spin resonance and the effects of slow motions in complex fluids.

A methodology for obtaining pure absorption two-dimensional electron spin resonance spectra is presented for the case of large inhomogeneous broadening and/or slow motions. For slow motions, the spectra consist of "complex Lorentzians" superimposed with complex weighting factors, presenting a challenge to obtaining absorption spectra. It is shown how absorption-type spectra can be recovered for the two-pulse COSY and SECSY experiments in such cases. For three-pulse 2D ELDOR experiments, absorption lineshapes can be obtained for the autopeaks, whereas the cross peaks would be of mixed-mode character, in general. However, for practical cases the dispersive components in the cross peaks will be relatively small. Theoretical and experimental absorption spectra are provided to illustrate the method and to show the improved resolution obtained from absorption lineshapes. In particular, the variation in linewidths across a SECSY spectrum, which is a key component in elucidating motional dynamics, is clearly rendered in the pure absorption mode. A convenient method for introducing the necessary phase corrections for the slow-motional spectra is also provided.

Absorption↗
PubMed1995

Ozone-reactive absorption by pulmonary epithelial lining fluid constituents.

Previous studies have suggested that the rate of inhaled O3 absorption from the intrapulmonary gas phase is principally mediated by reaction-dependent mechanisms rather than by physical solubility, tissue diffusion, or blood flow (Postlethwait et al., 1994, Toxicol. Appl. Pharmacol. 125, 77-89). The initial site of interaction between O3 and the lung surface occurs at the gas/liquid interface of the epithelial lining fluid (ELF). Therefore, we investigated (a) whether reactive uptake by ELF constituents could account for pulmonary uptake and (b) whether selected constituents acted as O3-specific absorption targets. Rat ELF was harvested by bronchoalveolar lavage. By injecting the same lavage fluid a second [(BALF)2] and/or third [(BALF)3] time into fresh lungs, a more concentrated form of ELF was obtained. Controlled quasi-steady-state exposures (O3 in air; 30-min duration) of cell-free BALF and model substrates (reduced glutathione, GSH) were utilized. Results were based on temperature-specific fractional and normalized uptake rates (r). We observed the following: (1) Buffer pH substantially influenced O3 absorption by GSH but by BALF only modestly. (2) Uptake displayed significant [BALF] and [GSH] dependence. (3) Fractional uptake decreased (BALF and GSH) with increasing [O3] although absolute uptake increased. (4) Absorption demonstrated temperature dependence. Arrhenius plots [ln(r) vs 1/T] were used to compute activation energies (Ea) and Q10. (BALF)1 Ea = 3387 cal/g mol with Q10 = 1.20. GSH (1 mM) Ea = 2240 with Q10 = 1.13. (5) Increasing flow reduced fractional uptake in a nonlinear fashion. (6) Dialysis (1000-molecular-weight cutoff) reduced uptake by (BALF)1 moderately (-30%). Sulfhydryl depletion produced minimal effect (-10%), while ascorbate depletion (-37%) and combined sulfhydryl and ascorbate depletion (-39%) were the most effective. Treatments produced lesser effects on (BALF)3. We conclude that the pH, aqueous substrate, and temperature-dependence and the Ea and Q10 are consistent with reaction-dependent O3 uptake by ELF. The analogous absorption characteristic between the ELF and intact lung (temperature, [O3], contact time) suggests that the ELF represents the primary site for O3-reactive absorption. Reduced sulfhydryls do not appear to substantially interact with inhaled O3. Principal absorption targets may include ascorbate, phospholipids, and other moderate to large molecular weight constituents.

Absorption↗
PubMed2000

Caco-2 cell permeability vs human gastrointestinal absorption: QSPR analysis.

The aim of this study is to elucidate quantitative structure-permeability relationship (QSPR) of various organic molecules through Caco-2 cells, and to ascertain the relationship between gastrointestinal (GI) absorption in humans and Caco-2 cell permeability. Caco-2 cell permeability and human GI absorption data were obtained from the literature. The maximum hydrogen bond-forming capacity corrected for intra-molecular H-bonding (Hbc) and Lien's QSAR model were used in this study. The latest CQSAR software was utilized in calculating the logarithm of partition coefficient in octanol/water (Clog P) and in deriving all regression equations. For 51 compounds, a significant correlation was obtained between Caco-2 cell permeability (log Pcaco-2) and Hbc, octanol/PBS (phosphate buffered saline, pH 7.4) distribution coefficient (log Doct), log MW and an indicator variable (I) for the charge, with a correlation coefficient of 0.797. When these compounds were divided into three subgroups, namely neutral, cationic and anionic compounds, much better correlations (r = 0.968, 0.915 and 0.931, respectively) were obtained using different combinations of various physico-chemical parameters. A plot of human GI absorption vs. Caco-2 cell permeability obtained from different laboratories reveals that Caco-2 cell permeability cannot be used to precisely predict human GI absorption for compounds with Pcaco-2 below 5 x 10(-6) cm/s, due to interlaboratory and experimental variabilities, and the lack of a simple correlation between human GI absorption and Caco-2 cell permeability. Caco-2 cell permeability may be estimated from the structures of drug molecules using the above-mentioned physicochemical parameters. In general, for compounds with Pcaco-2 above 5 x 10(-6) cm/s, human GI absorption ranges from 50 to 100%. This is generally acceptable for development into oral dosage form. For the compounds with Pcaco-2 below 5 x 10(-6) cm/s, careful interpretation of caco-2 cell permeability and use of internal standard for comparison are recommended. Otherwise, good drug candidates may be excluded due to incorrectly predicted poor absorption.

Caco-2 Cells↗
PubMed1988

Changes in intravesical pressure during irrigating fluid absorption in transurethral prostatic surgery.

Continuous recording of intravesical pressure (IVP) and incremental volumetric measurements of irrigating fluid absorption were performed during 37 transurethral resections of the prostate (TUR). Absorption which resulted in concomitant dilutional changes in peripheral blood, indicating intravascular absorption, was associated with prolongation of the time required to increase the IVP. There was an inverse relation between the change in maximum IVP and the rate of irrigating fluid absorption. Absorption that did not result in concomitant dilutional changes in peripheral blood, indicating extravascular absorption, was associated with similar changes in IVP parameters but the critical pressure for absorption was lower.

Absorption↗
PubMed1993

Correlates of intestinal calcium absorption in women 10 years past the menopause.

Because intestinal calcium absorption may be an important independent determinant of calcium balance and therefore bone mass, we have studied this factor and other potential predictors in 196 healthy postmenopausal women. Gut calcium absorption was measured in each subject by a stable strontium method and expressed as a fractional absorption. The fractional absorption was significantly negatively correlated with years since menopause (YSM) (r = -0.15 P < 0.05) and dietary calcium intake (r = -0.15 P < 0.05), and significantly positively correlated with 24-hour urine calcium excretion (r = 0.31 P < 0.001) and body mass index (r = 0.20 P < 0.01). Apart from YSM, these factors remained as correlates in multiple regression analysis; the standardized regression coefficient was largest for 24-hour urine calcium excretion (0.32). Fractional absorption of calcium was not correlated with vertebral bone density. Thus, intestinal calcium absorption, although falling with increasing menopausal age and increasing calcium intake, is best correlated with the urine calcium excretion. This indicates either that gut calcium absorption is regulated in response to the magnitude of the urine calcium excretion or that the kidney maintains calcium balance by excreting what is absorbed by the intestine. The mechanisms whereby gut and renal calcium handling are correlated are uncertain.

Absorptiometry, Photon↗
PubMed1995

Methylated beta-cyclodextrins are able to improve the nasal absorption of salmon calcitonin.

The absorption enhancing effect of methylated beta-cyclodextrins on the nasal absorption of salmon calcitonin (sCT) was studied in rats and rabbits. The nasal absorption of sCT following administration without additives was low in both species. The absorption in rats could be largely improved by coadministration of cyclodextrins as apparent from the effect on serum calcium concentrations. Trimethyl-beta-cyclodextrin (TM beta CD), at a concentration of 5% (w/v), was the least potent enhancer. Randomly methylated-beta-cyclodextrin (RM beta CD) and dimethyl-beta-cyclodextrin (DM beta CD), all at a concentration of 5% (w/v), were almost equally effective in decreasing serum calcium levels, and the hypocalcemic responses were similar to those of i.v. and s.c. injected sCT. Absorption enhancement was already achieved with 1% DM beta CD added to the nasal formulations. In rabbits, only the effect of DM beta CD on the nasal sCT absorption was investigated. A total serum calcium decrement in 4 hours of 9.4 +/- 3.9% (mean +/- SD) was observed following nasal administration of 12.6 IU/kg sCT with 5% DM beta CD, comparable to that of i.v.-injected sCT. In conclusion, the methylated cyclodextrins DM beta CD and RM beta CD are suitable absorption enhancers for nasal sCT administration, which is expected to have a clinical impact on the therapy with calcitonin.

Absorption↗
PubMed1987

Effects of lead, zinc and copper absorption on peripheral nerve conduction in metal workers.

To examine the antagonistic effects of lead, zinc and copper on the nervous system in man, we measured maximal motor and sensory conduction velocities (MCV and SCV, respectively) in the distal radial and median nerves in 20 gun metal founders with asymptomatically increased absorption of these metals [blood lead concentrations ranged from 16 to 64 micrograms/dl (mean 42)]; and analyzed metal effects on nerve conduction by multiple regression analysis. The MCVs in the radial and median nerves and the SCV in the forearm segment of the median nerve were significantly slowed; indicators of lead absorption (urinary delta-aminolevulinic acid and coproporphyrin) were inversely correlated with the SCV in the radial nerve. The SCVs in the radial nerve and in the hand segment of the median nerve, which were not significantly slowed, were positively related to indicators of copper absorption (plasma or erythrocyte copper). The SCV in the radial nerve was also positively related to the indicator of zinc absorption (plasma zinc); similarly, the MCVs in the radial and median nerves were positively related to the indicators of zinc absorption (erythrocyte or urinary zinc). These findings suggest that copper and zinc antagonize the subclinical effects of lead on peripheral nerve conduction velocities; the conduction velocity in the distal radial nerve is sensitive not only to asymptomatic lead absorption but also to zinc and copper absorption.

Absorption↗
PubMed1976

Increased intestinal absorption in the rat caused by sodium lauryl sulphate, and its possible relation to the cAMP system.

The increases in the absorption of ouabain, phenolsulphonphthalein and pralidoxime caused by 17 mM sodium lauryl sulphate (SLS) from jejunal loops of anaesthetized rats were significantly reduced if sodium and chloride (Briseid et al., 1974) or chloride and bicarbonate were replaced by other ions in the loop fluid. Separate substitutions of sodium, chloride of bicarbonate did not significantly alter the SLS-caused absorption, except that the substitution of choline for sodium reduced the absorption of pralidoxime, both in the presence and in the absence of SLS. The increases in the absorption of phenolsulphonphthalein and pralidoxime caused by SLS were potentiated by theophylline (25 mM) and reduced by imidazole (25 mM). The addition of dibutyryl cyclic AMP (2.5 mM) to the loop fluid increased this absorption of the test substances. This effect was reduced by imidazole, but under the experimental conditions it was not potentiated by theophylline. Determinations of cyclic AMP in the rat intestinal mucosa showed that the level of this substance was significantly higher in the presence than in the absence of SLS. The experimental conditions were as described for the absorption experiments. It is concluded that the data obtained support the idea of an increased level of cyclic AMP as the main basis for the effect of SLS on the absorption.

Animals↗
PubMed1983

Drug absorption by the rat jejunum perfused in situ. Dissociation from the pH-partition theory and role of microclimate-pH and unstirred layer.

In anaesthetized rats the rate of appearance of benzoic acid and aminopyrine in jejunal venous blood was measured; the pH of the luminal perfusion solution was varied between 4 and 10.5. The pH-absorption curves were less steep than predicted by the unmodified pH-partition theory. A reduction of the mucosal unstirred layer thickness by means of the segmented-flow technique considerably increased the absorption rate without essentially changing the shape of the pH-absorption curves. The pH at the surface of the jejunal mucosa was 6.0, 6.5, 6.6, and 8.0 for luminal solutions of pH 4.0, 6.0, 8.0, and 10.8, respectively. From the absorption data the microclimate-pH was calculated which would explain best the observed pH-absorption curves. These calculated pH-values correspond well to the values measured at the mucosal surface. Therefore, it was concluded that a microclimate-pH caused the deviation of the intestinal pH-absorption curves of benzoic acid and aminopyrine from the prediction of the unmodified pH-partition theory. The mucosal unstirred layer represented only a considerable permeation resistance and was not responsible for the deviating shape of the pH-absorption curves.

Aminopyrine↗
PubMed1982

Inter-relationships between the absorptions of hydrocortisone, sodium, water and actively transported organic solutes in the human jejunum.

The effect of intraluminal hydrocortisone (100 mg/l) on sodium and water transport in the small intestine was investigated by jejunal perfusion (flow rate 15 ml/min) of healthy subjects with normal saline and saline containing 56 mmol/l galactose or alanine. Minimal absorption of sodium and water occurred with normal saline and did not change significantly in the presence of hydrocortisone. Galactose and alanine enhanced sodium and water absorption and further significant increases occurred in the presence of hydrocortisone. Glucocorticoid induced increases in absorption were detected within 20-30 min, while plasma cortisol concentrations were in the normal range. 43% of the perfused dose of hydrocortisone was absorbed with normal saline (p less than 0.01). There was a significant positive correlation (p less than 0.0025) between hydrocortisone and water absorption. Thus, in the presence of actively absorbed organic solutes, hydrocortisone rapidly increased sodium absorption and the concurrent increase in water absorption appears to have facilitated passive absorption of hydrocortisone.

Adult↗
PubMed1980

Effect of feeding a high protein diet on solute-coupled water absorption from rat colon.

Using an in vivo sac technique, net transport of water, Na, Cl and K was studied in the colon ascendens of rats fed either a high carbohydrate (HC) or high protein (HP) diet, since water intake is elevated in HP-rats. The ligated colon sacs were filled with isotonic Krebs-Henseleit solution. Net Na and Cl absorption rates related to 1 g intestinal dry weight were 46% and 30% higher in HP-rats compared with HC-rats. Net water absorption in HP-rats exceeded that in HC-rats by 115%. Therefore the ratio between net water absorption and net absorption of solutes was higher in HP-rats than in HC-rats, and thus the hypertonicity of the absorbate was lower in the HP-rats. There was a net secretion of K in both groups of rats to about the same extent. Experiments with 22Na indicate that the increased net Na absorption in HP-rats was due to an increased unidirectional Na transport from the lumen to the blood side of the colon. The group difference in the ratio between net absorption of water and solutes might be a manifestation of regulatory mechanism controlling intestinal water absorption.

Animals↗
PubMed1994

Direct and quantitative vitamin B12 absorption measurement in patients with disorders in the distal part of the bowel. Comparison of stool spot test [SST] with whole body counting in patients with ileal pelvic reservoir, ileostomy or Crohn's disease.

Direct and quantitative vitamin B12 absorption studies were performed in 25 patients with disorders in the distal small intestine using whole body counting as the gold standard. Simultaneously, vitamin B12 absorption was also determined by the more simple stool spot test (SST) which incorporates 51CrCl3 as a nonabsorbable marker. The SST provided a reliable direct and quantitative measure of vitamin B12 absorption in patients with previous ileal resections due to Crohn's disease (CD) (n = 7) as compared with whole body counting. In ulcerative colitis (UC) patients with either an ileal pelvic reservoir (n = 10) or a conventional ileostomy (n = 8), markedly shorter bowel transit times and absence of colon may have hindered sufficient mixture of the tracer and marker isotopes which could explain the false absorption values according to the SST in single patients. Therefore, an intact colon and a near-normal bowel transit time seem to be essential for performance of the SST. Whole body counting showed, as expected, that all CD patients except one had decreased vitamin B12 absorption (median 23%; range 3-39%) (normally > 35%). In UC patients with ileostomy, only one had a markedly decreased vitamin B12 absorption, two borderline normal values, while the rest had normal values (median 54%, range 15-76%). All UC patients with ileal pelvic reservoir had normal vitamin B12 absorption values (median 40.5%, range 36-87%). We conclude that vitamin B12 substitution therapy is probably required in patients with CD with ileal resection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Pharmacokinetics of ibuprofen in man IV: absorption and disposition.

Fifteen normal male volunteers received 400, 800, and 1200 mg doses of ibuprofen as 1, 2, or 3 tablets, respectively, in crossover fashion, then 420 mg in solution form during the fourth week. Plasma concentration of ibuprofen was measured by an HPLC method. Individual subject concentration-time (C,t) data following the solution were analyzed by two different methods, and results unequivocally indicated the open two compartment model with first order absorption. However, the computer fitting of both arithmetic and geometric mean concentrations led to a different model. A method was developed to obtain absorption data (fraction of drug absorbed, Fa, versus time) for a multicompartmental system from oral data alone, without intravenous data. The method assumes that Vp is constant intrasubject and that absorption is complete following administration of both the solution and tablets. The method was successfully applied to the ibuprofen tablet data. It was shown also that such a method is necessary to obtain ibuprofen absorption data since intrasubject variation of the microscopic rate constants k12, k21, and kel (as reflected by the intrasubject variation of the hybrid rate parameters lambda 1 and lambda 2 or beta and alpha) is of the same order of magnitude as intersubject variation. Absorption of ibuprofen from tablets was shown not to be simple first order as for the solution. The absorption profiles following one tablet were S-shaped, while those following 2 or 3 tablets had partial linear segments indicating zero order absorption.

Absorption↗