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Chemotherapy-induced intestinal mucositis is a severe side effect contributing to reduced quality of life and premature death in cancer patients. Despite a high incidence, a thorough mechanistic understanding of its pathophysiology and effective supportive therapies are lacking. The main objective of this rat study was to determine how 10 mg/kg doxorubicin, a common chemotherapeutic, affected jejunal function and morphology over time (6, 24, 72, or 168 h). The secondary objective was to determine if the type of dosing administration (intraperitoneal or intravenous) affected the severity of mucositis or plasma exposure of the doxorubicin. Morphology, proliferation and apoptosis, and jejunal permeability of mannitol were examined using histology, immunohistochemistry, and single-pass intestinal perfusion, respectively. Villus height was reduced by 40% after 72 h, preceded at 24 h by a 75% decrease in proliferation and a sixfold increase in apoptosis. Villus height recovered completely after 168 h. Mucosal permeability of mannitol decreased after 6, 24, and 168 h. There were no differences in intestinal injury or plasma exposure after intraperitoneal or intravenous doxorubicin dosing. This study provides an insight into the progression of chemotherapy-induced intestinal mucositis and associated cellular mucosal processes. Knowledge from this in vivo rat model can facilitate development of preventive and supportive therapies for cancer patients.

Chemotherapy-induced intestinal mucositis is a severe side effect contributing to reduced quality of life and premature death in cancer patients. Despite a high incidence, a thorough mechanistic understanding of its pathophysiology and effective supportive therapies are lacking. The main objective of this rat study was to determine how 10 mg/kg doxorubicin, a common chemotherapeutic, affected jejunal function and morphology over time (6, 24, 72, or 168 h). The secondary objective was to determine if the type of dosing administration (intraperitoneal or intravenous) affected the severity of mucositis or plasma exposure of the doxorubicin. Morphology, proliferation and apoptosis, and jejunal permeability of mannitol were examined using histology, immunohistochemistry, and single-pass intestinal perfusion, respectively. Villus height was reduced by 40% after 72 h, preceded at 24 h by a 75% decrease in proliferation and a sixfold increase in apoptosis. Villus height recovered completely after 168 h. Mucosal permeability of mannitol decreased after 6, 24, and 168 h. There were no differences in intestinal injury or plasma exposure after intraperitoneal or intravenous doxorubicin dosing. This study provides an insight into the progression of chemotherapy-induced intestinal mucositis and associated cellular mucosal processes. Knowledge from this in vivo rat model can facilitate development of preventive and supportive therapies for cancer patients.

ObjectiveThe objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI).DesignRandomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden.MethodsSixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness).ResultsIn stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure.ConclusionsThis long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added.A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance.Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition.According to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time.

The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the β-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F(abs). The effective permeabilities (P(eff)) of sotalol and metoprolol, a FDA standard for the low/high P(eff) class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P(eff) at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P(eff) value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F(abs). In conclusion, we have shown that, in fact, there is no discrepancy between P(eff) and F(abs) in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.

The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome p450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes.The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed.Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively.Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation.

To determine the human jejunal permeability of cimetidine and ranitidine using a regional jejunal perfusion approach, and to integrate such determinations with previous efforts to establish a baseline correlation between permeability and fraction dose absorbed in humans for soluble drugs.A sterile multi-channel perfusion tube, Loc-I-Gut, was inserted orally and positioned in the proximal region of the jejunum. A solution containing cimetidine or ranitidine and phenylalanine, propranolol, PEG 400, and PEG 4000 was perfused through a 10 cm jejunal segment in 6 and 8 subjects, respectively.The mean Peff (+/- se) of cimetidine and ranitidine averaged over both phases were 0.30 (0.045) and 0.27 (0.062) x 10(-4) cm/s, respectively, and the differences between the two were found to be statistically insignificant. The mean permeabilities for propranolol, phenylalanine, and PEG 400 averaged over both phases and studies were 3.88 (0.72), 3.36 (0.50), and 0.56 (0.08) x 10(-4) cm/s, respectively. The differences in permeability for a given marker were not significant between phases or between the two studies.The 10-fold lower permeabilities found for cimetidine and ranitidine in this study, compared to propranolol and phenylalanine, appear to be consistent with their less than complete absorption in humans.

To compare solubility and dissolution rate of hydrocortisone in aspirated human intestinal fluids (HIFs) with simulated intestinal fluids (SIFs) and buffer.Solubility and flux from a rotating disk of hydrocortisone were measured. The bile salt content, pH and osmotic pressure were determined in HIFs.In fasted state the solubility of hydrocortisone was higher in HIFs than in the buffer and SIFs. The flux of hydrocortisone in HIFs was similar to the flux in the buffer but lower than the flux in SIFs at fasted state. Addition of intestinal surfactants in SIFs increased solubility and flux at both fasted and fed state. The increase in solubility was caused by micelle formation in SIFs. The increase in flux may partly be explained by increased solubility. The bile salt content of the HIFs did not correlate with the solubility or the flux but pH in the HIFs seems to have some effect on the components of the HIFs resulting in increased solubility.It is possible to perform comparable dissolution tests in HIFs and SIFs. The lack of correlation between the results in HIFs and the bile salt content may be explained by the relatively low lipophilicity of the model drug.

Chitosans are potent nontoxic absorption enhancers after nasal administration but their effects on the intestinal epithelium in vivo has not been studied in detail. In this study, the effects of chitosans with varying molecular weights and degrees of acetylation on the absorption of a poorly absorbed model drug (atenolol) were studied in intestinal epithelial cell layers with or without a mucus layer and in an in situ perfusion model of rat ileum. The effects of the chitosans on epithelial morphology and release of lactate dehydrogenase (LDH) into the perfusate were investigated in the in situ model. The chitosans had pronounced effects on the permeability of mucus-free Caco-2 layers and enhanced the permeation of atenolol 10- to 15-fold, with different absorption kinetics for different chitosans, in accordance with previous results. In contrast, enhancement of atenolol absorption through rat ileum was modest. LDH release from the tissues perfused with chitosans did not increase, indicating that the chitosans were used at nontoxic concentrations. Morphological examination of the perfused ileal tissues revealed more mucus discharge from the tissues exposed to chitosans than from controls, which suggested that the discharged mucus may inhibit the binding of chitosan to the epithelial surface and hence decrease the absorption-enhancing effect. This hypothesis was supported by studies with intestinal epithelial HT29-H goblet cells covered with a mucus layer. The binding of chitosan to the epithelial cell surface and subsequent absorption-enhancing effects were significantly reduced in mucus-covered HT29-H cultures. When the mucus layer was removed prior to the addition of chitosan, the cell surface binding and absorption-enhancing effects of the chitosans were increased. We conclude that the modest absorption-enhancing effects of unformulated chitosan solutions in the perfused rat ileum are a result of the mucus barrier in this tissue. This effect may be overcome by increasing the local concentrations of both chitosan and drug, i.e,. through formulation of the chitosan into a particulate dosage form.

The main purpose of this rat study was to investigate the effect of rifampicin on the effective permeability (P(eff)) of R/S-verapamil in the rat jejunum. In addition the effect on metabolism of R/S-verapamil to R/S-norverapamil was examined. In situ single-pass perfusions of the rat jejunum were performed in animals pretreated with oral rifampicin (250 mg/kg/day) or saline (control) over various time periods (1, 4, 7, and 14 days). The jejunal P(eff) of each of the enantiomers of verapamil and D-glucose was estimated. The appearance ratios of the CYP3A-formed metabolites R- and S-norverapamil were also estimated in the outlet jejunal perfusate. The jejunal P(eff) of both R- and S-verapamil decreased as an effect of the oral pretreatment with rifampicin. The appearance of R- and S-norverapamil in the jejunum was also affected by the oral pretreatment with rifampicin, with increasing concentrations of R/S-norverapamil being evident after 14 days of rifampicin pretreatment. There was no stereoselectivity in either the P(eff) of R- and S-verapamil or the metabolic appearance of R- and S-norverapamil. Treatment with oral rifampicin decreased the P(eff) of R/S-verapamil, which is in accordance with an induction of P-glycoprotein activity in the apical enterocyte membrane. The increase in appearance of R/S-norverapamil in jejunum is in accordance with an induction of CYP3A metabolism in the rat.

To investigate the relation between intestinal effective permeability (P(eff)) and surface activity of fluvastatin and verapamil.P(eff)-values were determined for fluvastatin, antipyrine and D-glucose following colon perfusions in the rat in situ. The perfusion solitions differed regarding concentrations of fluvastatin (0-2500 microM) and surface tension (58.9-43.7 mN/m). A cellulose derivative, ethyl-(hydroxyethyl) cellulose (EHEC), was added to lower the surface tension of one of the perfusion solutions. The surface tension of perfusion solutions containing R/S-verapamil (8-814 microM) and R/S-verapamil + chlorpromazine (814 microM + 10 mM) were related to the corresponding P(eff)-values from the literature.The P(eff)of fluvastatin correlated inversely (r2 = 0.985, p0.05) with the surface tension of the perfusion solutions below the critical micelle concentration (CMC, 1 mM). Decreasing the surface tension with EHEC increased the P(eff) of fluvastatin by 36% (p0.001), but not to the extent anticipated from the correlation between the P(eff) and the surface tension. EHEC also increased the P(eff) of antipyrine by 49% (p0.01 ) but not for D-glucose. The P(eff) of R/S-verapamil correlated inversely with the surface tension (r2 = 0.980, p0.001).The ability of fluvastatin to decrease the surface tension at the membrane surface can partly explain the concentration dependent colonic P(eff) of fluvastatin. This study shows that the surface activity of the drug molecule itself is an important physicochemical factor that should be taken into consideration when evaluating drug absorption studies performed in vitro or in situ.

Spironolactone (SP), a specific aldosterone antagonist, is used as a potassium sparing diuretic to reduce pulmonary oedema in premature infants suffering from bronchopulmonary dysplasia. In neonates oral medication is given through a nasogastric tube making liquid formulations preferable. Lacking suitable liquid preparations, powder papers prepared from commercial tablets are presently used, often causing obstruction of nasogastric tubes and loss of a variable part of the dose. Water-soluble derivatives of s-cyclodextrin have therefore been considered for the solubilization of SP in order to formulate a safe liquid preparation, which would also provide more concistent delivery of SP (Totterman et al. 1997, Kaukonen et al. 1997).

The purpose of this human intestinal perfusion study was to investigate the transport and metabolism of R/S-verapamil in the human jejunum (in vivo).A regional single-pass perfusion of the jejunum was performed using a Loc-I-Gut perfusion tube in 12 healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods each of 100 min. The inlet concentrations of verapamil were 4.0 and 40 mg/l in period one and two, respectively.The effective jejunal permeability (Peff) of both R- and S-verapamil increased (p0.05) when the inlet concentration was increased consistent with saturation of an efflux mechanism. However, both R- and S-verapamil had high intestinal Peff, consistent with complete absorption. The Peff of antipyrine also increased, but there was no difference in the Peff for D-glucose in the two periods. The appearance of R/S-norverapamil in the intestinal perfusate leaving the jejunal segment was non-linear, presumably due to saturation of the CYP3A4 metabolism.The increased Peff in parallel with increased entering drug concentration is most likely due to saturable efflux by P-glycoprotein(s) in the human intestine.

To study intestinal transport and metabolism of three new mu-selective tetrapeptide enkephalin analogues, LEF537, LEF553 and TAPP. These peptides are stabilized against enzymatic hydrolysis by having a D-amino acid in position 2 and a blocked COOH-terminal.We used a single-pass perfusion technique to study the transport of the peptides in rat jejunum. To reduce luminal and/or brush-border metabolism during the perfusion we used protease inhibitors (Pefabloc SC, bestatin and thiorphan). The rate of metabolism was studied by incubations in rat jejunal homogenate, rat jejunal fluid and human gastric and jejunal fluid with and without these inhibitors.The jejunal permeabilities (Peff) of the peptides were 0.43-0.78 x 10(-4) cm/s without inhibitors and 0.09-0.45 x 10(-4) cm/s in presence of the inhibitors. All three peptides were rather rapidly degraded by enzymes in rat jejunal homogenate with half-lives of between 11.9 +/- 0.5 and 31.7 +/- 1.5 min. The addition of inhibitors to the homogenate prolonged the half-lives substantially for LEF553 (167 +/- 35 min) and TAPP (147 +/- 2 min), but only slightly for LEF537 (16.4 +/- 0.5 min). LEF553 and TAPP were both hydrolyzed in rat and human jejunal fluid, while LEF537 was metabolized less in these fluids. When LEF553 and TAPP were incubated with intestinal fluid in the presence of inhibitors, metabolism was almost completely inhibited. There was no metabolism for any of the peptides in human gastric juice.The replacement of the terminal free carboxylic group with an amide group did not increase the stability of the peptides in jejunal tissue enough to allow successful oral drug delivery.

To determine the human jejunal permeabilities of compounds utilizing different transport mechanisms using a regional perfusion approach and to establish a standard procedure for determining drug permeability class to be used for the establishment of drug product bioequivalence standards.Six healthy male volunteers participated in this study. A multi-lumen perfusion tube was inserted orally and positioned in the proximal region of the jejunum. A solution containing piroxicam, phenylalanine, propranolol, PEG 400 and PEG 4000 was perfused through the intestinal segment at a rate of 3.0 ml/min. Perfusate samples were quantitatively collected every 10 minutes for two 100 minute periods with an intermediate wash out period to determine intra and intersubject variation.The mean P(eff) (+/-SD) of piroxicam, phenylalanine, propranolol, and PEG 400 were 10.40 +/- 5.93, 6.67 +/- 3.42, 3.59 +/- 1.60, 0.80 0.46 x 10(-4) cm/sec, respectively. The coefficient of variation for the intersubject variability, first and second perfusion periods were: piroxicam, 60.5% and 57.1%; phenylalanine, 52.8% and 57.8%; propranolol, 62.1% and 44.6%; and PEG 400, 81.7% and 42.3%, indicating a slightly lower CV for the second perfusion period in the same subject. The intrasubject CV's between the two perfusion periods were: 19.4%, 21.3%, 23.6% and 41.0% respectively, indicating a smaller intraindividual variation for all compounds studied.Piroxicam, a nonpolar drug exhibited the highest permeability of the compounds studied. The intrasubject CV was lower than the intersubject CV, indicating consistent permeability estimation within subjects. The methodology is useful for permeability estimation regardless of absorption mechanism and can be used to establish a consistent data base of human permeabilities for estimation of human drug absorption and for establishing the biopharmaceutic permeability class of drugs.

To chemically characterize the fluids available for drug dissolution in the upper gastrointestinal tract during the fasted state in humans, and to examine variations and potential gender differences regarding the physico-chemical properties of these fluids.Twenty-four healthy volunteers, 12 females and 12 males, were intubated, and fluids from the stomach and upper jejunum were collected separately. Bulk pH, osmolality, electrolytes and total concentrations of bile acids and proteins were assessed. To study intraindividual variations, eleven of the individuals were studied on more than one occasion.The stomach and upper jejunal fluids varied significantly in all the measured entities, except the total concentration of proteins. The intraindividual variability was pronounced in some of the individuals, both in the stomach and the upper jejunum. We did not, however, observe any gender differences.This study demonstrates the complex nature of the fluids available for drug dissolution in the stomach and the upper small intestine in humans. The results can be used when designing a more physiological in vitro dissolution media representative for the fasted state. When designing such a medium, we suggest that gender differences not be taken into account.

Our main aim is to determine the effective intestinal permeability (Peff) in the rat jejunum in situ for 10 compounds with different absorption mechanisms and a broad range of physico chemical properties, and then compare them with corresponding historical human in vivo Peff values.The rat Peff coefficients are determined using an in situ perfusion model in anaesthetized animals. The perfusion flow rate used is 0.2 ml/min, which is 10 times lower than that used in humans. The viability of the method is assessed by testing the physiological function of the rat intestine during perfusions.The Peff for passively absorbed compounds is on average 3.6 times higher in humans compared to rats (Peff, man = 3.6 x Peff.rat+ 0.03.10(-4); R]2 = 1.00). Solutes with carrier-mediated absorption deviate from this relationship, which indicates that an absolute scaling of active processes from animal to man is difficult, and therefore needs further investigation. The fraction absorbed of drugs after oral administration in humans (fa) can be estimated from 1-e-(-2.Peff,man t rex/r.2.8).Rat and human jejunum Peff-estimates of passively absorbed solutes correlate highly, and both can be used with precision to predict in vivo oral absorption in man. The carrier-mediated transport requires scaling between the models, since the transport maximum and/or substrate specificity might differ. Finally, we emphasize the absolute necessity of including marker compounds for continuous monitoring of intestinal viability.

Hydrophilic and charged solutes have a lower membrane permeability which is due to a lower partition into the lipid membrane (low solubility in the membrane phase) and/or a slower transcellular diffusion coefficient. They are therefore anticipated to be absorbed through the paracellular route, which is a consequence of diffusion and a convective volume flow through the water-filled intercellular space.Two approaches have been used to investigate the mechanisms underlying the paracellular drug transport across the intestinal mucosa: (a) including water transport by exposing the apical side of the epithelium with a hypotonic solution, and (b) stimulated paracellular transport by widening of tight junction and increased water absorption as a consequence of the sodium-coupled transport of nutrients.Among the first studies that recognized this fluid flux dependent transmucosal transport of drugs, was one published by OschenfahrtWinne in 1973 and the one by Kitazawa et al. in 1975. During the last two decades the importance of this paracellular route for drug delivery have been explored in vitro and in situ.The limits concerning molecular weight, shape, ionization and the effect of physiological stimulants, such as luminal concentrations of nutrients, osmolality and motility, are currently under investigation. However, recently published in vivo human data by ourselves and others indicate that the promising results obtained in vitro and in situ for various hydrophilic compounds might not be valid in quantitative aspects in humans, especially not for drugs with a molecular weight over 200.

In vivo permeability measurements of drugs in the colonic/rectal region in humans are difficult. A new instrument for the perfusion of a defined and closed segment in the colon/rectum was developed. The objective of this study was to evaluate its use for studying drug absorption mechanisms in the human rectum and to investigate the effect of transmucosal water absorption on drug permeability. Six healthy subjects participated at 2 separate occasions by using a modified system for segmental rectal perfusion. The system consisted of a multichannel tube with inflatable balloons and was endoscopically introduced into the rectum. The technique was considered acceptable by the following criteria; (a) high and reproducible recovery of PEG 4000, (b) stable residence time of the solution within the test segment, (c) flux of electrolytes that agrees with previous reports, (d) mass-balance absorption of antipyrine across the rectal barrier, (e) and good acceptability to the subjects. The permeability of antipyrine in the rectal region was increased by inducing net water absorption. D-glucose was not absorbed during any study periods. The present technique is valuable for studying drug absorption from the human rectum.

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Food ingestion can influence the absorption of levodopa in the intestine and thereby contribute to fluctuations of motor functions in Parkinson patients. Obstruction of the active transport of levodopa by amino acids can be one factor. Paracellular drug absorption, a route proposed to be influenced by net transport of water across the intestinal epithelium, might occur for a small and hydrophilic drug such as levodopa. In the present study we studied how luminal L-leucine (60 mmol/L), alone or combined with hypotonicity, might stimulate net water absorption, and levodopa uptake in the human small intestine, since this possibly can contribute to the variable intestinal absorption of levodopa. The Loc-I-Gut perfusion technique was used in 10 healthy volunteers to study the effects of induced net fluid absorption on the small intestinal absorption of levodopa (2.5 mmol/L). An induced net fluid absorption was observed only when L-leucine was combined with a hypoosmolar perfusion solution. However, this did not enhance the intestinal permeability of levodopa. In conclusion, we suggest that the variability in the absorption of levodopa in Parkinson's disease cannot be explained by differences in transmucosal water flux in the human small intestine.

Intestinal release of inflammatory mediators and permeation of macromolecules were studied in patients suffering from Crohn's disease, celiac disease and food intolerance with the use of a system for segmental intestinal perfusion. Drug absorption and ion and bicarbonate transport were also studied in healthy subjects. Patients with Crohn's disease of the distal ileum revealed an increased release of inflammatory agents into the lumen of the proximal jejunum. Luminal provocation with different antigens in cases of celiac disease and food intolerance not only activated cells in the intestinal mucosa but also increased the leakage from plasma and lymph. Studies of drug absorption elucidated the kinetics of drug transport from intestine to plasma, and basal neurologic effects on ion and bicarbonate transport were determined.

This study examined the pharmacokinetics of levodopa and carbidopa in the rat after different modes of administration. The drugs were given simultaneously by the intravenous, intraarterial, oral, duodenal, and intraperitoneal routes, as single doses. The ratio of levodopa to carbidopa given was always 4:1. Two iv doses (5 and 15 mg/kg of levodopa) were given to test for nonlinearity. Three ip doses of levodopa were given (5, 7.5, and 15 mg/kg), and the 15 mg/kg dose was given in three volumes (2, 4, and 20 mL/kg). One oral dose and two intraduodenal doses of 15 mg/kg were given. The drugs were dissolved in saline in one of the intraduodenal doses and suspended in 1.8% methylcellulose in the other. The elimination of levodopa was nonlinear. There was a comparatively high degree of interindividual variability in absorption with the oral route, but this was substantially reduced when levodopa was given intraduodenally. There was also much less variability with the intraperitoneal route compared to the oral, and the degree of absorption was generally high. There was a significantly higher extent and slower rate of absorption when levodopa was administered ip in a large volume of vehicle. These results suggest that the oral route may not be the optimal method of delivering levodopa to patients who have a fluctuating response and that a continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative.

Pafenolol is a beta-blocker with unusual oral absorption properties. The blood concentration-time profile exhibits two peaks, and the bioavailability is low and dose dependent because of incomplete and nonlinear intestinal uptake. We addressed the question whether the intestinal absorption of pafenolol was affected by bile depletion in the gut lumen of rats. Further, the hypothesis that variable gastric emptying accounts for double peaks in blood was tested by duodenal administration of pafenolol. Following intraduodenal administration to rats with intact bile secretion, double peaks were observed in the blood concentration-time curve. The bioavailability was 6.8 +/- 0.7% for the low dose (1 mumol/kg) and increased significantly to 28 +/- 10% following the high duodenal dose (25 mumol/kg). These blood concentration-time profiles exclude interrupted gastric emptying as cause of the twin peaks. In bile duct-cannulated rats the intestinal absorption of the low dose (1 mumol/kg) was still poor (F = 10.7 +/- 5.5%) and the blood concentration-time profile contained two peaks. Following administration of a high duodenal dose (25 mumol/kg) to rats with an almost bile-free small intestine, the absorption rate increased and the double-peak phenomenon disappeared in five of seven rats, while the bioavailability increased significantly, to 62 +/- 27%. These results suggest that the low bioavailability of pafenolol is due to a complexation between bile and pafenolol in the gut lumen, preventing intestinal uptake in the major part of the small intestine. Further, such complex formation in the intestinal lumen may be the underlying mechanism of the double peaks observed in the blood concentration-time profile.

The elimination of [3H]pafenolol and metabolites was investigated in fasted and fed rats. Separate groups received intravenous doses (0.3 and 3.0 mumol/kg) and oral doses (1 and 25 mumol/kg). After iv administration of pafenolol, the excretion of unchanged drug into urine and feces was about 50 and 25-30% of the given dose, respectively. The predominating mechanism for the excretion of pafenolol into feces was intestinal excretion (exsorption) directly from blood into gut lumen, since only about 3% of a given iv dose was recovered as pafenolol in the bile. When the oral dose was raised from 1 to 25 mumol/kg, the mean (+/- SD) bioavailability, calculated from urine data, increased from 14 +/- 9 to 30 +/- 11% (P0.05) in the starved rats and from 14 +/- 3 to 16 +/- 3% in the fed animals. In parallel, the fraction absorbed from the gut (fa) increased from 19 +/- 9 to 31 +/- 10% in the starved rats and from 16 +/- 4 to 19 +/- 5% in the fed animals, respectively. This indicates that the low bioavailability is due primarily to poor intestinal uptake.

Pafenolol is a beta 1-adrenoreceptor antagonist exhibiting some interesting oral absorption properties in both rat and humans. The blood concentration-time profile exhibits two peaks, and the bioavailability is low and dose-dependent due to an incomplete and nonlinear intestinal uptake. The origin of the presystemic metabolism was studied in rats after oral and intraperitoneal administration of tritium-labeled pafenolol with reference to the intravenous route by means of urinary excretion data of pafenolol and metabolites specifically assayed by HPLC and radioisotope detection. The oral-bioavailability increased from 15.8 +/- 4.1% (1.0 mumol/kg) to 33.3 +/- 5.8% (25 mumol/kg, p0.001). This was primarily due to a change in the fraction of the absorbed dose (fa) from 21.9 +/- 4.6 to 39.5 +/- 7.9% (p0.01). The bioavailability following an intraperitoneal dose was almost complete indicating that the presystemic metabolism was due to gut wall metabolism. Saturation of the presystemic metabolism contributed only by approximately 15-20% to the 2-fold increase of bioavailability. This clearly indicates that the underlying mechanism for the low and dose-dependent bioavailability was an incomplete and nonlinear intestinal uptake. The metabolic pattern showed that at least eight metabolites are formed in the rat. One of these is an alpha-OH pafenolol, identified as the main metabolite in human urine by mass spectrometry.

The gastrointestinal absorption characteristics of pafenolol following oral administration as a solution in man and rat has previously been found to be a double-peak phenomenon and exhibited dose-dependent bioavailability, despite negligible presystemic metabolism. In both man and rat the first peak appeared approximately 0.5-1 hr postdose and the second, more pronounced peak 3-4 hr postdose. In rat more than 90% of the available dose was absorbed during the second peak. In the present study we investigated the absorption of a solution of pafenolol in rats after intrajejunal and intraileal administration. The resulting blood concentration-time profile of pafenolol exhibited one peak only; the extent of absorption was similar to that observed when the same dose was given orally. The small intestinal transit time of the 14C-PEG 4000 solution was found to be more than 3 hr. The transit rate was higher in the proximal part of the small intestine compared to the more distal part, where the transit of the solution was staggered. In conclusion, the results of the intestinal transit time investigation and the administrations of pafenolol at different levels of the alimentary tract indicate that pafenolol is a drug with a specific absorption site located in the ileocolonic region.

Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (+/- SD) fraction of phenazone absorbed calculated from perfusion data was 51 +/- 12% (3 ml/min), 64 +/- 19% (3 ml/min), and 42 +/- 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 +/- 16%, 51 +/- 19%, and 38 +/- 26%, respectively. The effective permeability of phenazone was 5.3 +/- 2.5, 11 +/- 6.8, and 11 +/- 12 (x 10(4) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.(ABSTRACT TRUNCATED AT 250 WORDS)