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Drug absorption is a very complex process that manifests itself through potential interaction with a host of physicochemical and physiological variables. Some factors that may affect the absorption processes include presystemic metabolism/efflux, the "absorption window" along the gastrointestinal tract, disease states, demographics (gender, age, ethnicity), and biopharmaceutical classification of solid dosage forms. Despite the complexity of the absorption processes, the analysis of the absorption kinetic data is mostly empirical, and the assumption of first-order absorption is axiomatic. Nevertheless, we often encounter irregular drug absorption profiles (such as double-peak, absorption window-type absorption profiles, etc.) that cannot be satisfactorily described by a simple first-order absorption process. The selection of an inappropriate absorption model would result in the misspecification of the pharmacokinetic model and subsequent erroneous prediction of the dosing regimen. This article presents several pharmacokinetic strategies in analyzing typical and atypical absorption profiles. The atypical absorption profiles discussed in this article include parallel first-order absorption, mixed zero-order and first-order absorption, Weibull-type absorption, absorption window with or without Michaelis-Menton absorption, time-dependent absorption, and inverse Gaussian density absorption. In any event, intravenous drug concentration-time data are generally needed to avoid the ambiguousness in the absorption analyses.
Contribution of different gut segments to plant sterol absorption, adaptation of plant sterol absorption after partial small bowel resection, and effects of gut transplantation (necessitates extrinsic autonomic denervation and lymphatic disruption) on plant sterol biodynamics are unclear. We studied the consequences of massive proximal small bowel resection and autotransplantation of the remaining ileum on the adaptive absorption and biodynamics of plant sterols. Dietary, fecal, biliary, hepatic and plasma plant sterols, fecal elimination and absorption of cholesterol, small bowel morphology, and intestinal transit were determined before (n = 5) and at 4, 8, and 14 wk after resection of the proximal 75% of the jejunoileum (n = 15) and autotransplantation of the remaining ileum (n = 15) or transection (n = 5). Proximal gut resection significantly reduced cholesterol absorption efficiency; percentage absorption and biliary secretion of plant sterols; plasma, biliary and hepatic campesterol-to-cholesterol proportions; and sitosterol proportions in plasma and bile. Autotransplantation of the remaining ileum further significantly decreased cholesterol absorption efficiency; percentage absorption and biliary secretion of campesterol; campesterol proportions in plasma, bile and liver; and plasma proportions of sitosterol while increasing fecal excretion of neutral and acidic steroids. Plasma proportions of the two plant sterols, but absorption of just campesterol, were gradually improved with increasing cholesterol absorption and villus height after proximal gut resection; the same result was observed to a lesser degree after ileal autotransplantation. In addition, significant positive correlations were found between percentage cholesterol and campesterol absorption and the plasma plant sterol proportions in both proximal resection groups, between campesterol absorption and ileal villus height in the resection group, and between campesterol absorption and intestinal transit time in the autotransplantation group. In conclusion, plasma campesterol and sitosterol closely reflect absorption of cholesterol and plant sterols from intact and autotransplanted ileum during adaptation to proximal gut resection. A loss of proximal gut absorptive surface impairs cholesterol and campesterol absorption more than sitosterol absorption, the latter being apparently less dependent on available jejunal villus surface area.
1. The modification of iron absorption from Fe(III)EDTA by agents known to promote or inhibit absorption was examined in 101 volunteer multiparous Indian women. Fe absorption from Fe(III)EDTA was compared with absorption of intrinsic food Fe in a further twenty-eight subjects. Finally the urinary excretion of radio-Fe after oral administration of 59Fe(III)EDTA was studied in twenty-four subjects and evidence of intraluminal exchange of Fe was examined. 2. Fe absorption from maize porridge fortified with Fe(III)EDTA was more than twice that from porridge fortified with FeSO4 . 7H2O. 3. Although bran decreased Fe absorption from FeSO4 . 7H2O approximately 11-fold, it had no significant effect on Fe absorption from Fe(III)EDTA. Nevertheless tea, which is a more potent inhibitor of Fe absorption, decreased absorption from Fe(III)EDTA 7-fold. 4. Fe absorption from Fe(III)EDTA given in water was only increased 40% by addition of 3 mol ascorbic acid/mol Fe but by 7-fold when the relative proportions were increased to 6:1. This enhancing effect was blunted when the Fe(III)EDTA was given with maize porridge. In these circumstances, an ascorbate:iron value of 3:1 (which doubles absorption from FeSO4 . 7H2O) produced no significant increase in Fe absorption, while a value of 6:1 produced only a 2 . 5-fold increase. 5. Fe absorption from Fe(III)EDTA was not altered by addition of maize porridge unless ascorbic acid was present. 6. Less than 1% of 59Fe administered as 59Fe(III)EDTA was excreted in the urine and there was no inverse relationship between Fe absorption and the amounts excreted (r 0 . 58, P less than 0 . 05). 7. Isotope exchange between 59Fe(III)EDTA and 59FeSO4 . 7H2O was demonstrated by finding a similar relative value for the two isotopes in urine and erythrocytes when the two labelled compounds were given together orally. This finding was confirmed by in vitro studies, which showed enhanced 59Fe solubilization from 59FeSO4 . 7H2O in maize porridge when unlabelled Fe(III)EDTA was added. 8. Although Fe absorption from Fe(III)EDTA was marginally higher it appeared to form a common pool with intrinsic food iron in most studies. It is postulated that the mechanism whereby Fe(III)EDTA forms a common pool with intrinsic food Fe differs from that occurring with simple Fe salts. When Fe is present in the chelated form it remains in solution and is relatively well absorbed because it is protected from inhibitory ligands. Simple Fe salts, however, are not similarly protected and are absorbed as poorly as the intrinsic food Fe. 9. It is concluded that Fe(III)EDTA may be a useful compound for food fortification of cereals because the Fe is well absorbed and utilized for haemoglobin synthesis. The substances in cereals which inhibit absorption of simple Fe salts do not appear to inhibit absorption of Fe from Fe(III)EDTA.
Recent studies have suggested that certain gastrointestinal peptides exert a trophic effect on the small intestine. We chose to evaluate the effect of glucagon and cholecystokinin-octapeptide (CCK-OP) on absorption of substrates in both developing and mature small intestine. Developing small intestine was evaluated in a rat fetal intestine transplant model, and mature rat small intestine was studied in in situ but isolated 10 cm segments of jejunum and ileum. Glucagon, 10 micrograms/kg/day, and CCK-OP, 45 micrograms/kg/day, were delivered continuously for 14 days through a subcutaneous osmotic pump. Intestinal absorption was determined with labeled substrates (14C-galactose and 14C-glycine) by a recirculation perfusion technique. Absorption results were expressed as percentage increase over control. The fetal intestine response to glucagon infusion was a 13% rise in galactose absorption and a 27% rise in glycine absorption. After CCK-OP infusion, fetal galactose absorption was 11% and glycine absorption rose 17%. Mature jejunal galactose absorption rose 53% and glycine absorption rose 55% after glucagon infusion. The ileal response to glucagon was a 271% rise in galactose absorption (p less than 0.05) and a 21% increase in glycine absorption. Infusion of CCK-OP decreased jejunal galactose absorption 3% but increased glycine absorption 41%. The ileal response was a 224% increase in galactose absorption (p less than 0.05) and a 19% increase in glycine absorption. Our data suggest that chronic administration of glucagon and CCK-OP can increase substrate absorption in developing and mature rat small intestine. Perhaps manipulation of the gastrointestinal hormone environment may result in increased absorption in man.
Dermal exposure to jet fuels has received increased attention with the recent release of newer fuels with novel performance additives. The purpose of these studies was to assess the percutaneous absorption and cutaneous disposition of topically applied (25 microl/5 cm(2)) neat Jet-A, JP-8, and JP-8(100) jet fuels by monitoring the absorptive flux of the marker components 14C naphthalene and (3)H dodecane simultaneously applied nonoccluded to isolated perfused porcine skin flaps (IPPSF) (n = 4). Absorption of 14C hexadecane was estimated from JP-8 fuel. Absorption and disposition of naphthalene and dodecane were also monitored using a nonvolatile JP-8 fraction reflecting exposure to residual fuel that might occur 24 h after a jet fuel spill. In all studies, perfusate, stratum corneum, and skin concentrations were measured over 5 h. Naphthalene absorption had a clear peak absorptive flux at less than 1 h, while dodecane and hexadecane had prolonged, albeit significantly lower, absorption flux profiles. Within JP-8, the rank order of absorption for all marker components was (mean +/- SEM % dose) naphthalene (1.17 +/- 0.07) > dodecane (0.63 +/- 0.04) > hexadecane (0.18 +/- 0.08). In contrast, deposition within dosed skin showed the reverse pattern. Naphthalene absorption into perfusate was similar across all fuel types, however total penetration into and through skin was highest with JP-8(100). Dodecane absorption and total penetration was greatest from JP-8. Absorption of both markers from aged JP-8 was lower than other fuels, yet the ratio of skin deposition to absorption was greatest for this treatment group. In most exposure scenarios, absorption into perfusate did not directly correlate to residual skin concentrations. These studies demonstrated different absorption profiles for the three marker compounds, differential effects of jet fuel types on naphthalene and dodecane absorption, and uncoupling of perfusate absorption from skin disposition.
BACKGROUND/AIMS: Active absorption of glucose stimulates passive absorption of small solutes. Part of this effect may be caused by glucose-induced water absorption. Increased water absorption can enhance passive solute absorption by solvent drag and by passive diffusion if the luminal solute concentration increases as water is removed from the lumen. The purpose of this research was to quantitate the contribution of these two forces when glucose enhances the absorption of L-xylose. METHODS: The effect of solvent drag on L-xylose absorption was determined by measuring the effect of water absorption stimulated by hypotonicity on L-xylose absorption when the L-xylose concentration was constant. The effect of diffusion on L-xylose absorption was determined by measuring the effect of L-xylose concentration on L-xylose absorption when water absorption was nil. RESULTS: Glucose increased L-xylose absorption by 1.8 mmol.h-1 x 30 cm-1 (from 1.4 to 3.2 mmol.h-1 x 30 cm-1). The increase attributable to solvent drag was 1.03 mmol.h-1 x 30 cm-1; the increase attributable to passive diffusion was 0.75 mmol.h-1 x 30 cm-1. CONCLUSIONS: When glucose stimulates the passive absorption of L-xylose, 57% of the increase can be attributed to solvent drag and 42% to passive diffusion. Because the combined effect of these two forces can account for 99% of the observed effect, virtually all of the glucose effect on L-xylose absorption can be explained by glucose-induced water absorption.
In the postprandial period, augmentation of absorption of water, electrolytes, and taurocholate is believed to occur in the ileum. The role of extrinsic innervation in this postprandial augmentation has not been well studied and may be an important concept in small bowel transplantation. Our aim was to investigate extrinsic neural mechanisms mediating postprandial absorptive patterns. The study hypothesis was that postprandial augmentation of absorption in the ileum is blunted in transplanted (extrinsically denervated) bowel. Ileal absorption was studied in six dogs with an 80-cm in situ ileal segment via a triple-lumen perfusion technique using an iso-osmolar, ileal-like electrolyte solution alone and containing either glucose 2.5 mM, glutamine 2.5 mM, oleic acid 5 mM, or taurocholate 5 mM. Net absorptive fluxes of each substrate, as well as water and electrolytes, were measured in both the fasted state and after a 400-Kcal mixed meal before and at 2 and 12 weeks after our validated model of complete extrinsic denervation of the jejunoileum. At baseline, there were no differences in absorption of water, electrolytes, or any nutrient postprandially compared with the fasted state. Two weeks after extrinsic denervation, absorption of glucose at both 1 and 2 hours postprandially was decreased compared with absorption during fasting. Glutamine absorption was also decreased at 2 hours postprandially. At 12 weeks after extrinsic denervation, net postprandial absorption of glucose and glutamine returned toward normal and was not different from fasting absorption. No differences were noted in postprandial absorption of oleic acid or taurocholate at any time point. Decreases in absorption of nutrients postprandially after extrinsic denervation (which is necessitated by small bowel transplantation) may play an important role in post-transplant enteric absorptive dysfunction. The previously described postprandial augmentation in net absorption may be a function of enterically isolated gut and does not appear to occur in the in situ ileum.
Ileal water and electrolyte absorption exceed jejunal absorption in both the basal and meal-stimulated states. The purposes of these experiments were to determine: (1) if luminal bile acids alter basal or meal-stimulated intestinal absorption, and (2) if there is site specificity or meal stimulation of intestinal bile acid absorption. Twenty-five centimeters of canine proximal jejunal and distal ileal Thiry-Vella fistulas were constructed. Simultaneous jejunal and ileal absorption studies (n = 88) were performed with a luminal perfusate containing polyethylene glycol labeled with radioactive carbon-14 to calculate the absorption of water, electrolytes, and the bile acid taurocholate (TC). In group 1, there was no TC in the luminal perfusate, whereas in group 2, 10 mM of TC was present in the luminal perfusate. Half of the observations were performed after a meal stimulus, which consisted of an orally ingested, 480-kcal mixed nutrient meal. Intraluminal TC did not affect basal or meal-stimulated water or electrolyte absorption. In both the basal and meal-stimulated states, ileal absorption of water, electrolytes, and TC significantly exceeded jejunal absorption (p < 0.05). A meal significantly stimulated water and electrolyte absorption in both the jejunum and ileum, but it stimulated absorption of TC in the ileum only (p < 0.05). Intraluminal TC does not alter basal or meal-stimulated intestinal water and electrolyte absorption. A meal stimulates increased water and electrolyte absorption in both the jejunum and the ileum, but it stimulates bile acid absorption in the ileum only. Bile acid absorption is site specific and responsive to a meal stimulus.
Paracellular transport is thought to be a major absorptive pathway for small nutrient molecules. The authors used in vivo in situ perfusion of rat duodenum-proximal jejunum to examine paracellular transport using lactulose as a probe. They perfused solutions with a constant lactulose concentration but varied initial D-glucose concentration (range 12-176 mM) to open paracellular pathways and to increase water absorption, thereby optimizing potential for paracellular transport of lactulose and other solutes in its molecular weight range. All solutions contained sodium chloride to approach isotonicity. Water absorption was measured as the difference in weight of solution perfused and sample collected. Absorption of D-glucose increased with mean luminal D-glucose concentration, and water absorption more than doubled (from 0.12 +/- 0.03 to 0.26 +/- 0.05 mL/min per g dry wt of segment) as mean luminal glucose concentration was increased from 10 to 80 mM. Lactulose absorption was at the threshold of detection and did not correlate with D-glucose or water absorption. Expressed as percent per segment, D-glucose absorption ranged from 29-50%, and the lactulose absorption rate was 4-5%. The fraction of D-glucose absorption that could be attributed to lactulose absorptive pathways was 12% at the highest rate of water absorption. In conclusion, based on lactulose as a probe, under conditions of opening tight junctions by D-glucose, the paracellular component of D-glucose absorption was of the order of 1/10 of total D-glucose absorption (ie, not a major absorptive pathway.
In vivo angiotensin II (ANG II) exerts a dose-dependent dual action upon intestinal absorption. At low doses, ANG II stimulates sodium (Na) and water absorption from all intestinal areas. At high doses, ANG II inhibits absorption. The stimulation of jejunal absorption in response to ANG II is secondary to the release of norepinephrine (NE) from enteric sympathetic nerves. ANG II may act either within the brain or at the sympathetic nerve terminal to liberate NE. In contrast, the inhibition of absorption in response to ANG II is due to enteric prostaglandin production. At the present time it is unclear whether the changes in absorption in response to ANG II in vivo are due to changes in transport processes or secondary to alterations in enteric hemodynamics. ANG II also exerts a dose-dependent dual action on intestinal ion and water absorption in vitro. The mechanisms responsible for changes in absorption in vitro are unknown. However, since enteric sympathetic nerves are severed from their ganglia, it is unlikely that ANG II stimulates absorption in isolated preparations through release of NE. ANG II exerts a major control over intestinal absorption following volume depletion. The hormone controls colonic absorption through release of aldosterone and directly influences jejunal absorption via enteric sympathetic nerves. ANG II may control ileal absorption following volume depletion. All components of the renin-angiotensin system are present within the intestine. Furthermore, ANG II-like immunoreactivity is present within enteric nerves. The role of locally formed ANG II in the control of intestinal absorption has not been studied. Models illustrating the effect of ANG II on intestinal absorption are discussed.
The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when the doses were related to unit body surface area (BSA) but not on unit body weight, indicating similar interspecies absorptive capacity in terms of unit BSA. This finding may be partly rationalized by marked similarities in the reported solution transit time (2-3 hr) in the small intestine as well as in the calculated gross surface area of the small intestine per unit BSA (0.163 for rat and 0.132 for human). Contrary to the previous postulation of a specific absorption site, the drug was absorbed from different regions of the GI tract with apparent 1-hr absorption rates, studied by the in situ closed-loop method, in the following rank order: jejunum (34.6%) greater than duodenum (32.7%) greater than large intestine (20.1%) greater than ileum (18.0%) greater than stomach (12.4%). Different from the commonly assumed first-order absorption process, the intestinal loop absorption was concentration-dependent, suggesting a saturable mechanism. For example, the absorption rate at 0.008 mg/mL was higher than that at 0.2 mg/mL in ileal loops (61%, p less than 0.01) and jejunal loops (22%, p less than 0.1). In addition, the absorption rates at pH 6 and 7.4 were statistically identical, indicating a lack of ionization effect that is important in the passive absorption process. The solubility-limited absorption could probably be ruled out at doses below 2.55 mg/kg for rat and 125 mg for human in view of higher aqueous solubilities at 37 degrees C (e.g., 1.3 mg/mL at pH 7) found in the present study. Contrary to the previous hypothesis of low membrane permeability as a limiting factor for absorption, the "intrinsic" partition coefficient in 1-octanol/aqueous buffer was moderate, 0.6. Furthermore, the absorption in ileal and jejunal loops was enhanced by an apparent increase in mesenteric blood flow by caffeine. The existence of prolonged oral absorption in rats and humans is discussed.
Previous studies have shown that the disposition of cadmium (Cd) following oral administration is dosage dependent and may possibly be due to dosage-dependent intestinal absorption of Cd. Though extensively studied, the precise nature of Cd absorption by the intestine remains unclear. Similarly, the role of metallothionein (MT) in the intestinal absorption of Cd remains equivocal. The present study was designed (1) to characterize the intestinal absorption of Cd in the rat, and (2) to determine the role of MT in intestinal Cd absorption. The study has been conducted with an isolated intestinal loop preparation in situ, which allows direct measurement of intestinal absorption under nearly physiological conditions. Under urethane-induced anesthesia. Cd (0.1, 10, 100, 1000, or 10,000 micrograms/kg) was injected intraluminally into the isolated intestinal loop in situ and all mesenteric venous (portal) blood exiting from the loop was collected for 90 min. Absorption of Cd into the portal circulation was low at all dosages studied. The percentage of the dosage absorbed ranged from 0.09% at the 0.1 microgram/kg dosage to 3.4% at the 10,000 micrograms/kg dosage. At low dosages (0.1 and 10 micrograms/kg), little difference was noted in the fractional absorption of Cd (0.09 and 0.14% of the dosage, respectively). However, the fractional absorption of Cd was 10-fold greater in rats administered 100 micrograms Cd/kg (1.1% of the dosage). Administration of higher dosages of Cd (1000 and 10,000 micrograms/kg) further increased the percentage of the dosage absorbed (1.8 and 3.4%, respectively). To evaluate the role of MT in the intestinal absorption of Cd. rats were subcutaneously injected with zinc (Zn) for 4 days (30 mg/kg/day) and the absorption of an intermediate dosage of Cd (100 micrograms/kg) was subsequently assessed in situ. Zn pretreatment increased the endogenous concentration of MT in the intestine 25-fold. Following intraluminal administration. 93% of Cd in intestinal cytosol of Zn-treated rats was bound to MT whereas 40% of the cytosolic Cd was bound to MT in saline-treated (control) rats. Moreover, the amount of Cd in intestinal cytosol was 2-fold greater in Zn-treated rats than in control rats. However, the intestinal absorption of Cd in rats pretreated with Zn demonstrated no difference from that in saline-treated rats. These results indicate that the intestinal absorption of Cd is dosage independent at low dosages of Cd (less than 10 micrograms/kg) and dosage dependent at high dosages (greater than 10 micrograms/kg). Furthermore, saturation of intestinal MT is not a major determinant of the observed dosage-dependent absorption of Cd.
In general, absorption enhancing effects of various absorption enhancers were greater in the large intestine than those in the small intestinal regions. Therefore, the effectiveness of absorption enhancers is expected to be remarkably observed, if these enhancers can be delivered to the large intestine with some poorly absorbable drugs after oral administration. In this study, therefore, we examined whether chitosan capsules were effective for the colon-specific delivery of a certain absorption enhancer and can improve the absorption enhancing action of the absorption enhancer after oral administration. 5(6)-Carboxyfluorescein (CF) was used as a model drug to investigate the site-dependent effectiveness of various absorption enhancers by an in situ closed loop method. Sodium glycocholate (NaGC), n-dodecyl-beta-d-maltopyranoside (LM), sodium salicylate (NaSal) and sodium caprate (NaCap) were used as models of absorption enhancers in this study. Overall, the absorption enhancing effects of these enhancers for intestinal absorption of CF were greater in the colon than those in the jejunum and the ileum. Especially, among these enhancers tested in this study, LM showed much greater absorption enhancing effect in the colon than in the jejunum and the ileum. Therefore, LM was selected as a model absorption enhancer to examine the effect of chitosan capsules on the absorption enhancing effect of LM. When CF and LM were orally administered to rats using chitosan capsules, the plasma concentration of CF was much higher than those in other dosage forms including solution and gelatin capsules. Therefore, chitosan capsules may be useful carriers for colon-specific delivery of LM, thereby increasing its absorption enhancing effect from the intestinal membranes.
The effect of glucose on intestinal absorption of calcium was studied in the jejunum and ileum of control, diabetic (streptozotocin-induced), and insulin-treated diabetic rats. Intestinal absorption was determined in vivo using an in situ one-pass perfusion technique. In the jejunum of control and diabetic rats, net absorption and unidirectional lumen to mucosa flux of calcium and net absorption of water were significantly greater during perfusion of an isotonic NaCl solution, containing 15 mmol/L of glucose, than during perfusion of the same solution containing 15 mmol/L of mannitol instead of glucose. To determine if net absorption of calcium and water were related, the jejunum was perfused with a hypotonic solution (260 mosmol/kg) in separate groups of rats. Although net absorption of water was equivalent during perfusion of the hypotonic solution to that noted during perfusion of the isotonic glucose-containing solution, rate of absorption of calcium was not enhanced. Thus, it appeared that, if the enhancement in absorption of calcium by glucose was an effect on the passive absorption of calcium, it was through a mechanism not related to passive absorption of water. As expected, jejunal absorption of calcium was lower in diabetic than in control rats. Because in diabetic rats the metabolism of vitamin D to its active metabolite, 1,25-dihydroxy vitamin D, is defective, the enhancement in absorption of calcium by glucose did not appear to be due to a mechanism influenced by vitamin D metabolism. In the ileum, rate of absorption of calcium was lower than in the corresponding jejunum and was not significantly altered by the presence of glucose in the perfusion solution, by perfusion of a hypotonic solution, or by the diabetic state. The mechanism of action of glucose on calcium absorption in the jejunum needs to be studied further.