Sumatriptan Absorption from Different Regions of the Human Gastrointestinal Tract

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.     

Jejunal Absorption,Pharmacological Activity,and Pharmacokinetic Evaluation of Indomethacin-Loaded Poly(d,l-Lactide) and Poly(Isobutyl-Cyanoacrylate) Nanocapsules in Rats

The jejunal absorption of indomethacin nanocapsules was studied using an in vivo infusion technique. Jejunal absorption of indomethacin from the nanocapsules was slightly delayed as compared to a commercial indomethacin solution. The plasma and jejunal mucosa indomethacin concentrations were similar in both cases. However, the nanocapsules protected the rat jejunum from the ulcerating effect of indomethacin, probably by avoiding direct contact of the free drug with the surface of the mucosa. The pharmacokinetic profile of indomethacin nanocapsule formulations was compared to a solution of free drug following oral administration of 5 mg/kg in rats; no difference in the mean concentration–time profiles of the drug was observed. Blood levels of thromboxane showed a sustained biological activity, over a period of 24 hr, of indomethacin-loaded nanocapsules, relative to the drug in solution, following oral administration.     

Absorption and Presystemic Metabolism of Selegiline Hydrochloride at Different Regions in the Gastrointestinal Tract in Healthy Males

Purpose. The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. Methods. An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. Results. Selegiline exposure was greatest following administration to the stomach (~150% > duodenum or jejunum) and least in the terminal ileum (~33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (~18%) at the terminal ileum. Conclusions. The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.     

Gastrointestinal Transit and Distribution of Ranitidine in the Rat

Purpose. Ranitidine gastrointestinal distribution was examined in the rat small intestine after oral administration to determine whether intestinal transit or secretion (exsorption) may influence the appearance of secondary peaks in ranitidine serum concentration-time profiles. Methods. Male Sprague-Dawley rats received ranitidine (50 mg/kg) by oral gavage, and the mass of ranitidine recovered in all small intestinal segments (~12 cm each) was determined 30, 60, 90, or 120 min after administration. In a separate group of anesthetized rats, the small intestine was divided into two segments of equal length that were perfused with normal saline in a single-pass manner. Rats received an escalating, zero-order IV infusion of ranitidine for 30 min, and venous blood and intestinal effluent were collected over 90 min to quantitate ranitidine exsorption. Results. Thirty min after oral administration, >50% of the recovered ranitidine mass resided in the lower half of the small intestine in all rats. Ranitidine mass in 5 of 16 rats displayed a bimodal distribution with significant amounts of ranitidine recovered from the stomach 60 to 90 min after dosing. Ranitidine exsorption was more efficient from the lower jejunum and ileum than from the duodenum and upper jejunum. However, intestinal secretion of ranitidine was minor (5% of the IV dose). Conclusions. Ranitidine absorption from the lower ileum contributes significantly to systemic ranitidine concentrations before and during the time of the first concentration maximum. Separation of the drug mass into multiple boluses may contribute to secondary peaks in ranitidine concentration-time profiles. Exsorption did not contribute significantly to ranitidine distribution in the gastrointestinal tract.     

The Effect of Raising Gastric pH with Ranitidine on the Absorption and Elimination of Theophylline from a Sustained-Release Theophylline Tablet

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2–2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 × 100-mg immediate-release tablets, (b) 2 × 300-mg sustained-release theophylline tablets, and (c) 2 × 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P > 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.     

Effect of bupropion on cimetidine and ranitidine absorption in rats

Cimetidine and ranitidine absorption were studied in rats, alone or in combination with concurrent but separate bupropion oral administration. Blood samples were collected before and 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.5, and 6.0 h after dosing. In ranitidine-treated rats, an extra blood sample at 8 h was collected. Assays of cimetidine and ranitidine were carried out using a HPLC method. Mean cimetidine plasma concentrations on concurrent bupropion administration at 0.25 and 0.5 h were approximately 2 and 1.5 times compared to the control. Similarly, mean ranitidine plasma concentrations with bupropion combination at 0.25 and 0.5 h were significantly different and approximately 2 and 3 times higher. Time of maximum concentration for cimetidine and ranitidine on combination were reduced to almost half of the control value. However, only the time of maximum concentration for cimetidine showed statistically significant difference. No significant differences were observed between AUCs, maximum concentrations, and half-lives of cimetidine and ranitidine compared to their respective controls. The results suggest that concurrent bupropion administration may affect the rate but not the extent of absorption of cimetidine and ranitidine.     

Influence of digestive secretions and food on intestinal absorption of nicardipine

Summary The role of digestive absorption in the pharmacokinetics of nicardipine has been studied by the perfusion technique. Nicardipine (40 mg) was perfused in six healthy subjects at 5 ml/min for 2 h either in isotonic saline with (Experiment A) or without (B) an occlusive balloon isolating the test segment from digestive secretions, or in a nutrient solution (Experiment C). In Experiments A and B, 100% of nicardipine was absorbed from the jejunal lumen in a 25 cm test segment and in Experiment C it was slightly lower (94%). There was no relationship between the absorption of nicardipine and water movement or bile salt concentration in the jejunum.Nicardipine was already present in the first plasma sample taken after 15 min and the peak level was found at the end of the perfusion. The areas under the curves differed widely between subjects, because of interindividual variation in the first pass effect, but they were similar in Experiments A, B and C.The experimental data showed a good fit to a mode involving a two-phase absorption process. The first phase was associated with intestinal perfusion (zero order process) and the second with passage accross the intestinal wall (1st order process).In three further healthy subjects, nicardipine in saline was perfused in the jejunum and then in the ileum on consecutive days. Mean plasma levels over time were similar.The study showed that absorption of nicardipine both from the jejunum and the ileum was complete and was especially rapid. The food-induced change in the kinetics of absorption from the jejunum was too small to affect the pharmacokinetic parameters of nicardipine.     

Gastric persorption of bismuth from ranitidine bismuth citrate

Aim: To determine whether bismuth penetrates the gastric mucosa after dosing with ranitidine bismuth citrate. Methods: Twelve patients presenting with dyspepsia were randomized to receive either ranitidine bismuth citrate or placebo, 20–40 min prior to endoscopy. Biopsies were taken from four sites during endoscopy: the first and second parts of the duodenum, the antrum, and the body of the stomach. Biopsies were analysed by electron microscopy and X-ray microanalysis. Results: Bismuth particles were found to be interposed between epithelial cells in the antral mucosa of three of eight patients who were dosed with ranitidine bismuth citrate. Columns of bismuth particles could be tracked down the lamina propria and were seen to be surrounding blood vessels. Bismuth particles were observed in the inter- and intra-cellular channels of the endothelial cells of the blood vessels in the lamina propria and also close to the luminal surface of the endothelial cell. This process of persorption was similar to that described in a previous report of electron microscopy appearances of the gastric antrum after dosing with tripotassium dicitrato bismuthate, but was quantifiably smaller and not observed in all the patients dosed with ranitidine bismuth citrate. No penetration of the mucosa by bismuth particles was seen in the body of the stomach or the duodenum. Conclusion: Penetration of bismuth particles into the gastric mucosa may occur after oral dosing with ranitidine bismuth citrate.     

Influence of acid secretory status on absorption of omeprazole from enteric coated granules.

1. In order to study the absorption of omeprazole under normal acidic conditions in the stomach as well as when the granules are exposed to minimal gastric acid, eight healthy males were given 20 mg omeprazole as enteric coated (EC) granules either alone or 2 h after a ranitidine dose of 300 mg, respectively. 2. Blood samples were collected at intervals for 12 h following both omeprazole administrations. The pH was recorded during the first 4 h in half the subjects in each experiment to document the difference in pH during the absorption phase of omeprazole. 3. The area under the plasma concentration-time curve, AUC, of omeprazole was virtually the same irrespective of whether or not the granules were exposed to gastric acid. However, the maximum plasma concentration (Cmax) was higher and the time to reach Cmax was shorter when omeprazole was administered after a ranitidine dose. 4. It is concluded that gastric acidity has negligible influence on the AUC of omeprazole, which is directly correlated to the antisecretory effect, when administered as EC granules.     

Effect of food and ranitidine on saquinavir pharmacokinetics and gastric pH in healthy volunteers

STUDY OBJECTIVES: To assess the relative bioavailability of saquinavir after administration with ranitidine alone, ranitidine and food, and food alone; and to investigate the mechanism underlying the effects of pH and food on saquinavir absorption. DESIGN: Single-center, open-label, randomized, three-part crossover, pharmacokinetic pilot study. SETTING: General clinical research center in Scotland. SUBJECTS: Twelve healthy male volunteers. INTERVENTION: Each subject was given a single dose of saquinavir mesylate 600 mg with one of three randomly assigned treatments: ranitidine 150 mg on the evening before and 150 mg on the day of study drug administration, without food (treatment A); ranitidine 150 mg on the evening before and 150 mg on the day of study drug administration, with food (treatment B); and with food alone (treatment C, control). After a 7-day washout period between each of the interventions, subjects received the other two treatments. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken serially for 24 hours after each saquinavir dose, and gastric pH was measured during the 8 hours after dosing. Adverse events were monitored throughout the study. Single doses of saquinavir were well tolerated with or without ranitidine. Of the three treatments, the highest mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) for saquinavir occurred with treatment B; the lowest C(max) and AUC occurred with treatment A. Compared with treatment C (control), saquinavir's bioavailability was 15.9% (90% confidence interval [CI] 10-25%) after treatment A and 167% (90% CI 106-265%) after treatment B. Interindividual variability in both C(max) and AUC was slightly greater after treatments A and B than after treatment C. No correlation was found between pharmacokinetic parameters (C(max) and AUC) and gastric pH parameters, including maximum pH and pH at the time of drug delivery. CONCLUSION: Plasma concentrations of saquinavir were significantly higher when the drug was administered with food and ranitidine than when it was given with food alone. However, these increases were not related to changes in gastric pH caused by ranitidine. It can be postulated that food does not increase the bioavailability of saquinavir through its effect on gastric pH.     

A randomized crossover study investigating the influence of ranitidine or omeprazole on the pharmacokinetics of cephalexin monohydrate

Limited data characterize pharmacokinetic interactions between cephalexin and ranitidine, and no data exist for an interaction with proton pump inhibitors. The purpose of this study was to investigate the effects of ranitidine or omeprazole administration on the pharmacokinetics and pharmacodynamics of cephalexin. A randomized single- and multiple-dose crossover study was conducted in healthy subjects ingesting cephalexin before and after steady-state administration of ranitidine or omeprazole. Time-concentration profiles were determined and pharmacokinetic parameters were characterized using noncompartmental methods. Pharmacokinetic data were analyzed in accordance with the two 1-sided test for bioequivalence. The percentage of time that serum concentrations remain above the MIC(90) during the dosing interval (T > MIC(90)) for Streptococcus pyogenes and Staphylococcus aureus associated with the pharmacokinetic profiles was calculated. The coadministration of cephalexin with ranitidine or omeprazole resulted in relatively minor changes in C(max), AUC(infinity), t(1/2), or CL/F. t(max) was significantly prolonged when cephalexin was administered with ranitidine or omeprazole. Suboptimal T > MIC(90) was observed for cephalexin irrespective of acid suppression. Delay in absorption of cephalexin resulted in a decrease in the percentage of T > MIC(90) for certain acid-suppressive regimens and pathogen combinations. With the exception of an increase in t(max), there were no significant pharmacokinetic interactions between cephalexin and ranitidine or omeprazole. Delayed t(max) associated with acid suppression may result in a diminished T > MIC(90).     

Gastrointestinal absorption and metabolism of capsaicin and dihydrocapsaicin in rats

Gastrointestinal absorption of capsaicin and dihydrocapsaicin was studied in rats in vivo and in situ. Rapid absorption of capsaicin or dihydrocapsaicin from stomach and small intestine occurred in vivo. About 85% of the dose was absorbed in the gastrointestinal tract within 3 hr. In situ, within 60 min after the administration of capsaicin and dihydrocapsaicin into stomach, jejunum, and ileum, about 50, 80, and 70% of the respective dose had disappeared from the lumen. When 2,4-dinitrophenol or NaCN was added, no significant reduction in uptake of [3H]dihydrocapsaicin was observed in the jejunum. These results suggested that capsaicin and its analogs were absorbed by a nonactive process in jejunum. [3H]Dihydrocapsaicin was mainly absorbed via the portal system but not a mesenteric lymphangial one. The radioactivity in the portal blood was composed of 85% of [3H]dihydrocapsaicin and 15% of its metabolite (8-methyl nonanoic acid) bound to the albumin fraction. Dihydrocapsaicin-hydrolyzing enzyme activity was found in jejunal tissue. These results suggest that capsaicin and its analogs partly received a first-pass effect, i.e., metabolism of a compound following first absorption in the gastrointestinal tract. It is concluded that capsaicin and its analogs are readily transported to the portal vein through the gastrointestinal tract by a nonactive process and partly metabolized during absorption.     

Risedronate Gastrointestinal Absorption Is Independent of Site and Rate of Administration

Purpose. Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). Methods. Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. Results. Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. Conclusions. These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.     

Pharmacokinetics of piroxicam,a new nonsteroidal anti-inflammatory agent,under fasting and postprandial states in man

The kinetic disposition of piroxicam, under evaluation in man as a new anti-inflammatory drug, was studied in human volunteers given a single oral dose after both overnight fasting and food. Total absorption was uninfluenced by food intake, although the data indicate that food causes some delay in attainment of peak serum levels. The halflife of drug in plasma in the fasting subjects (37.5±2.4hr) was similar in both the fasting state and after food, suggesting that once-daily dosing may be appropriate for maintaining therapeutic plasma levels. Mean pharmacokinetic parameters for both studies in the fasting state and after meals are volume of distribution divided by availability, 0.140 or 0.136 liter/kg; total plasma clearance divided by availability, 2.68 or 3.12 ml/hr/kg. Approximately 10% of a single dose of piroxicam was eliminated in the urine within 8 days after oral drug administration. Renal clearance of the drug (0.28±0.10 ml/hr/kg) was 10.4% or less of plasma clearance, suggesting that piroxicam is extensively metabolized. In this study one subject showed a reduction in white blood count on the sixteenth day after a 60-mg dose; however, hematology values evaluated in both intraand intersubject comparisons did not show any other differences in the present study.This work was supported in part by a grant from Japan Rheumatoid Foundation (JRP).     

Human Jejunal Permeability of Two Polar Drugs: Cimetidine and Ranitidine

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Pharmacokinetic Modeling of Absorption Behavior of 9-Aminocamptothecin (9-AC) Released from Colon-specific HPMA Copolymer–9-AC Conjugate in Rats

Purpose To quantitate and predict colon-specific 9-aminocamptothecin (9-AC) release from the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer–9-AC conjugate and its absorption behavior after oral administration in rats. Methods Drug distribution in the gastrointestinal (GI) tract and the plasma concentration-time profile of 9-AC released from the HPMA copolymer conjugate were predicted using the degradation, transit, and absorption rate constants in cecum. The fate of 9-AC in cecum and liver was measured by in-situ cecum absorption and liver perfusion. Results Following oral administration of the conjugate, 9-AC was released rapidly in cecum. Based on the pharmacokinetic model, up to 60% of the dose was in the cecum at ~6 h, and 7% of the dose still remained there at 24 h. The predicted plasma concentration curve for released 9-AC after an oral dose of 3 mg/kg of 9-AC equivalent increased gradually and reached a peak of 98 nM at 7 h, then started decreasing slowly to 16 nM at 24 h. The bioavailability value was estimated as 0.31 after the first-pass elimination. Conclusions A pharmacokinetic model delineated the impact of GI transit, drug absorption rate, and first-pass metabolism on drug disposition following oral administration of HPMA copolymer–9-AC conjugate in rats.     

Use of the InteliSite® Capsule to Study Ranitidine Absorption from Various Sites Within the Human Intestinal Tract

Purpose. The purpose of this study was to evaluate the extent of ranitidine absorption from an externally activated drug-delivery system in two distinct regions of the intestine (jejunum and ileum) in healthy human volunteers. This investigation also was designed to evaluate the utility of the InteliSite ^® capsule for studying regional intestinal drug absorption in humans. Methods. The intestinal absorption of ranitidine from the jejunum and ileum was compared in eight, healthy volunteers in this open-label, two-way crossover study. In two of the eight volunteers, absorption from the colon also was studied. Subjects swallowed the capsule containing ranitidine solution (121 mg) and 100 Ci of ^99mTc-DTPA. The endcap of the capsule contained 20 Ci of ¹¹¹In-DTPA. At the desired intestinal site, the capsule was activated by the application of an external RF magnetic signal (6.78 MHz operating frequency) and the ranitidine solution was released. Blood samples were collected from a forearm vein for 12 hours after capsule activation. Results. The capsule released the ranitidine solution when activated in the jejunum, ileum and colon (visualized by the gamma camera). There was no difference in the extent of ranitidine absorption or ranitidine pharmacokinetics when the capsule was activated in the jejunum or ileum. Conclusions. This study demonstrates the utility of a novel, externally activated drug-delivery system to assess site-specific intestinal drug absorption in humans. Results indicate that use of the InteliSite ^® capsule method to evaluate site-specific intestinal ranitidine absorption in humans yields data similar to that obtained previously by means of oral intubation studies.     

Pharmacokinetics of acrivastine after oral and colonic administration

Six healthy male volunteers participated in this randomized, crossover open-label pharmacokinetic study consisting of two dosing segments separated by a washout period of at least 5 days. During each dosing segment, each volunteer received 12 mg of acrivastine, an investigational histamine H1-receptor antagonist, in a syrup form either orally or by colonic administration in random order. After oral and colonic administration, respectively, the following mean +/- SD pharmacokinetic parameters were obtained: Cmax 179 +/- 11 and 13.8 +/- 5.2 ng/ml; tmax, 0.85 +/- 0.13 and 3.60 +/- 0.56 hr; AUC0-12 hr, 576 +/- 57 and 104 +/- 46 hr.ng/ml. Differences between the oral and colonic administration for all three parameters were statistically significant (P less than 0.001). The mean +/- SD relative bioavailability of acrivastine from colonic compared to oral dosing was 0.18 +/- 0.09. It may be concluded, therefore, that appreciable absorption of acrivastine from the colon does not take place. These results suggest that comparison of pharmacokinetic profiles of some drugs after oral and colonic administration may be a useful technique for predicting bioavailability from a sustained release oral formulation.     

Effect of ketoconazole and rifampicin on the pharmacokinetics of ranitidine in healthy human volunteers: a possible role of P-glycoprotein

The aims of this study were to determine the effect of ketoconazole and rifampicin on the oral pharmacokinetics of ranitidine in human volunteers and to investigate the role of P-glycoprotein (P-gp) using in vitro systems. A randomized, placebo controlled crossover oral pharmacokinetic study was conducted in 12 healthy male human volunteers and in vitro (everted sac) and in situ (intestinal loop) studies were conducted in rats to study the role of P-gp. There was a statistically significant (p < 0.05) difference observed in the pharmacokinetic parameters C(max), AUC and MRT after pretreatment with rifampicin (600 mg orally once per day for 7 days). The C(max), AUC(0-infinity), and MRT were decreased by 53%, 52%, and 18%, respectively. Ketoconazole treatment (200 mg orally once per day for 5 days) increased the C(max), AUC(0-infinity) and T1/2 by 78%, 74%, and 56%, respectively, whereas T(max) was decreased by 31%. No statistically significant differences were observed in renal clearance (CLR) of ranitidine after treatment with either ketoconazole or rifampicin. Presence of ketoconazole significantly reduced the mean cumulative efflux concentrations (serosal to mucosal) of ranitidine to 35%, 41% and 55% in the duodenal, jejunum and ileal regions of the everted sacs, respectively, whereas, the mean cumulative efflux concentrations of ranitidine were increased by 14%, 36% and 25% in duodenal, jejunal and ileal regions of the rat small intestine, respectively, after pretreatment with rifampicin. The presence of ketoconazole improved the absorption of ranitidine significantly by increasing the percentage of total dose disappearing from the loops of duodenum, jejunum and ileum of rat small intestine by 82%, 84% and 85%, respectively. In contrast, treatment with rifampicin decreased the absorption of ranitidine by decreasing the percentage of total dose disappearing in duodenal, jejunal and ileal regions of the intestinal loops by 40%, 39% and 25%, respectively. Ranitidine was shown to be a P-gp substrate in vivo in human volunteers and it was found that oral bioavailability of ranitidine was influenced at the intestinal absorption phase.     

Applications and Simulations of a Discontinuous Oral Absorption Pharmacokinetic Model

Purpose. To illustrate the application of a discontinuous oral absorption model to cimetidine and ranitidine plasma concentration versus time data to demonstrate the use of the model for drugs which display discontinuous oral absorption profiles, and to illustrate the effect of various model parameters on plasma drug concentration versus time profiles and bioavailability. Methods. A discontinuous oral absorption model was used to fit ranitidine and cimetidine serum concentrations following oral and intravenous administration. The model was also used to simulate bioavailability and plasma concentrations versus time profiles for various parameter values. Results. Serum concentrations following administration of ranitidine and cimetidine were well described by the model, and parameter estimates obtained were in agreement with literature values. Simulations demonstrate the effects of various absorption parameters and gastrointestinal tract transit parameters on bioavailability and plasma concentration profiles. Conclusions. This discontinuous oral absorption pharmacokinetic model can be a useful tool in characterizing absorption phases, disposition, and bioavailability of drugs exhibiting two absorption peaks following oral administration.