The Rate and Extent of Oral Bioavailability versus the Rate and Extent of Oral Absorption: Clarification and Recommendation of Terminology

In the literature, the meanings of the terms oral absorption and oral bioavailability of drugs vary greatly. Absorption has been considered to take place at the mucosal membrane of the gastrointestinal (GI) tract. It has also been defined as the process from the site of drug administration to the site of measurement. In the latter definition, the extent of oral absorption depends on the extent of first-pass elimination in the gut wall and liver even though a drug may be completely absorbed from the GI tract. Moreover, these two terms have also been used interchangeably. Inconsistency in the definition of these two terms has led to varying interpretations of these terms among students, researchers and laymen, and such an inconsistency seems undesirable. Apparently because of these inconsistencies, improper correlations between the Caco-2 permeability or intestinal permeability and the oral bioavailability of drugs subject to extensive first-pass effect may have occurred. It is suggested that absorption be defined as movement of drug across the outer mucosal membranes of the GI tract, while bioavailability be defined as availability of drug to the general circulation or site of pharmacological actions. Since transit times (this may range from about 1 min to several hours) across enterocytes, liver, lungs, and the peripheral venous sampling tissue are virtually unknown for all drugs, this factor alone would favor the use of oral bioavailability rate rather than oral absorption rate in all routine studies.     

Effect of Pancreatico-Biliary Secretions and GI Transit Time on the Absorption and Pharmacokinetic Profile of Ranitidine in Humans

Purpose. Ranitidine plasma concentration vs. time profiles and the extent of ranitidine absorption were examined in the presence and absence of pancreatico-biliary secretions in order to elucidate factors which may contribute to secondary peaks after oral ranitidine administration. Methods. Ranitidine solution (300 mg) was administered to 4 fasting healthy subjects via an indwelling small-bore oroenteric tube located 16 cm distal to the pylorus. On 3 consecutive days, subjects randomly received ranitidine alone (control), ranitidine 10 min after 0.04 g/kg IV cholecystokinin (CCK) sufficient to cause gall bladder emptying into the duodenum, and ranitidine 30 min after inflation of an occlusive duodenal balloon located 10 cm distal to the pylorus to prevent pancreatico-biliary secretions from reaching the dosing port or beyond. Small bowel transit time (SBTT; min) was measured by breath H₂. Serial blood samples, obtained over 12 hours in each treatment, were analyzed by HPLC to determine ranitidine AUC_0–2(ng*h/mL), as well as C_max(ng/mL) and T_max(min) of the first and subsequent peaks, if subsequent peaks were observed. Results. Ranitidine AUC_0–2and C_max1, were not altered significantly by treatments; treatment effects on SBTT varied. Secondary peaks were observed in subjects #1 and #3 during the control treatment and subjects #2 and #4 during the CCK treatment. No secondary peaks were observed in any subject during the balloon treatment, and T_max1was delayed. Conclusions. Results support the hypothesis that pancreatico-biliary secretions (present in the intestinal lumen during control or CCK treatment) and gastrointestinal transit time may influence the occurrence of secondary peaks in ranitidine concentration vs. time profiles.     

Evaluation of a Targeted Prodrug Strategy to Enhance Oral Absorption of Poorly Water-Soluble Compounds

Purpose. The purpose of this research was to examine a targeted prodrug strategy to increase the absorption of a poorly water-soluble lipophilic compound. Methods. Three water-soluble prodrugs of Cam-4451 were synthesized. The amino acid (Cam-4562, Cam-4580) or phosphate (Cam-5223) ester prodrugs introduced moieties ionized at physiological pH and targeted intestinal brush-border membrane enzymes for reconversion to the parent. Selectivity for reconversion of the three prodrugs was examined in rat intestinal perfusate and brush-border membrane suspensions. Bioavailability of Cam-4451 in rats was evaluated after administering orally as the parent or as prodrugs in a cosolvent vehicle or in methylcellulose. Results. Cam-5223 was highly selective for reconversion at the brush-border, but was rapidly reconverted in intestinal perfusate. Cam-4562 was not as selective but was more stable in the perfusate, whereas Cam-4580 was neither selective nor stable. Oral bioavailability of Cam-4451 was 14% after dosing as the parent in the cosolvent vehicle, 39% and 46%, respectively, as Cam-4562 and Cam-5223. Oral bioavailability was only 3.6% when the parent was dosed in methylcellulose, whereas the bioavailability was 7-fold higher when dosed as the phosphate prodrug. Conclusions. Water-soluble prodrugs that target brush-border membrane enzymes for reconversion can be useful in improving drug oral bioavailability.     

Oral Absorption of D-Oligopeptides in Rats via the Paracellular Route

Purpose. This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers. Methods. The study series comprised eleven D-oligopeptides, designed not to be recognised by peptidases or transport proteins, and to have molecular weights between 222 and 406 daltons with different net electrical charges and composition of D-amino acids. All the peptides were [³H]-radiolabelled and analyzed by HPLC with radiometric detection. Bioavailability was estimated based on 24-hr urinary excretion of unchanged peptide after oral and intravenous administrations. Results. As expected, the series proved metabolically stable. Bioavailability was independent of oral dose when varied by a factor of 10,000, suggesting passive absorption. Whereas bioavailability decreased sharply from 30% to 1% with increasing molecular weight, net charge showed little, if any, effect on bioavailabilty. Conclusions. This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.     

Oral Absorption of Peptides: The Effect of Absorption Site and Enzyme Inhibition on the Systemic Availability of Metkephamid

In this study the intestinal degradation and absorption of a synthetic pentapeptide, metkephamid, were investigated in the rat by determination of its wall permeabilities in the small and large intestine and the extent and mechanism of its intestinal degradation. The peptide was metabolized in the gut wall through contact with membrane-bound enzymes in the brush border membrane. The extent of metabolic inactivation depended on the intestinal segment investigated and decreased in the axial direction. No metabolism was found in the colon. The dimensionless wall permeabilities (P _w*), determined by single-pass perfusion, were also site dependent. P _w* was highest in the ileum [1.91 ± 0.24, (SE); n = 4], followed by the jejunum (1.64 ± 0.34; n = 4) and the colon (0.67 ± 0.38; n = 4). Based on the permeability data alone and under the assumption of no presystemic metabolism, complete bioavailability would be predicted for metkephamid. However, following oral administration, the mean absolute bioavailability was only 0.22 ± 0.065% (n = 3), indicating the overall dominance of degradation in the absorption process. Thus future strategies in oral peptide delivery should focus on increasing the stability of the peptide in the intestine by modifying the peptide structure and/or delivering the compound to an intestinal segment showing little or no enzymatic degradation.     

Influence of Gastrointestinal Site of Drug Delivery on the Absorption Characteristics of Ranitidine

The absorption characteristics of ranitidine after delivery to three locations in the gastrointestinal tract were compared in an open-label study of eight healthy males. Subjects received ranitidine HCl (150 mg) for injection via a nasoenteric tube directly into their stomach, jejunum, or cecum sequentially in three separate periods (24 hr apart). Plasma samples were collected at periodic time intervals for 12 hr following each dosing and analyzed for ranitidine concentration by high-pressure liquid chromatography. Mean concentrations following cecal dosing were lower (P < 0.05) than concentrations following gastric or jejunal dosing at each sampling time except baseline. Mean concentrations following gastric and jejunal dosing were similar except at 2 hr (gastric > jejunal). Mean pharmacokinetic parameters for cecal administration were different (P < 0.05) from either the gastric or the jejunal periods with the exception of T_max. There was no difference in any pharmacokinetic parameter after gastric or jejunal dosing. The relative bioavailability after cecal administration was less than 15% of that observed after administration into the stomach or jejunum. Additionally, Wagner-Nelson analysis indicated that the rate of ranitidine absorption was much slower following cecal administration than after gastric or jejunal dosing. Two plasma concentration peaks were observed in three of eight subjects after gastric dosing, in eight of eight subjects after jejunal dosing, and in zero of eight subjects after cecal dosing. These data demonstrate that the absorption profile of ranitidine is equivalent, in extent and duration, after delivery to the stomach or jejunum, while absorption from the cecum is significantly less. In addition, the two plasma concentration peaks commonly seen with ranitidine administration are not secondary to variations in gastric emptying as has been hypothesized.     

Comparison of Oral Absorption and Bioavailability of Drugs Between Monkey and Human

Purpose. To compare the oral absorption and bioavailability of numerous drugs with a wide variety of physicochemical and pharmacological properties between humans and monkeys and to explore potential reasons for the findings. Methods. Data for fraction of dose absorbed (F _a) and oral absolute bioavailability (F) were obtained by an extensive Medline database search. Inclusion and exclusion criteria were the same as those reported in our previous studies. A total of 43 and 35 drugs were selected for F _a and F comparison, respectively. The time to reach peak concentration (t _max), total clearance, and nonrenal clearance were evaluated for 15, 28, and 13 drugs, respectively. Results. F _a values in monkeys were similar or identical to those in humans. Additionally, similar t _max values were seen in monkeys and humans at comparable doses, thus indicating comparable absorption kinetics between the two species. Conversely, F values in monkeys were generally lower with coumarin being a marked exception. Both total and nonrenal clearances were evaluated and found to be generally greater in monkeys, supporting a generally higher first-pass metabolism and lower F in this species. This was also supported by published data suggesting greater in vitro hepatic drug metabolism for monkeys as compared to humans. Conclusions. Monkeys appear to be a good predictor of F _a in humans. However, a generally lower F makes monkeys a potentially poor predictor of human F. Higher reported metabolic clearances and hepatic enzyme activities in monkeys may account for this observation.     

Impaired cimetidine absorption due to antacids and metoclopramide

Summary In 8 healthy subjects the absorption of cimetidine was investigated when given alone, together with 60 ml aluminium/magnesium hyroxyde containing antacid (neutralising capacity 26 mmol HCl/10 ml), and together with liquid metoclopramide 14 mg. The antacid significantly (P<0.01) reduced the bioavailability (area under the plasma level-time curve) of cimetidine, on average by one third. Metoclopramide also reduced the bioavailability by an average of 22%. The reductions were associated with significantly reduced excretion of cimetidine in urine. There was no change in the half-life or renal clearance of cimetidine, supporting the hypothesis of reduced gastrointestinal absorption. The results indicate that cimetidine and antacids should not be given together, and that the dose of cimetidine may have to be increased if it is administered concomitantly with metoclopramide.     

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.     

Lymphatic Absorption Is a Significant Contributor to the Subcutaneous Bioavailability of Insulin in a Sheep Model

Purpose: This study was conducted to explore the role of the peripheral lymphatics in insulin absorption following subcutaneous (SC) administration using a sheep model that allows continuous collection of peripheral lymph and simultaneous assessment of systemic bioavailability. Methods: In a parallel group design, soluble human insulin (0.5 IU/kg) was administered by bolus SC injection into the interdigital space of the hind leg of non-cannulated control sheep, and sheep in which the efferent popliteal lymph duct was cannulated. A separate group received a bolus IV injection (0.15 IU/kg). Blood was sampled from all animals, and lymph was collected continuously over 12 h post-dosing. Samples were assayed for insulin by ELISA. Results: The SC bioavailability of insulin in control sheep was 31.5 ± 3.2%, which was significantly higher than when the peripheral lymph was continuously collected (18.4 ± 1.7%). In the lymph-cannulated animals, 17.3 ± 1.0% of the dose was collected in peripheral lymph. Conclusions: Based on the direct measurement of insulin in regional lymph and on the decrease in the systemic bioavailability when regional lymph was continuously collected, the results demonstrate that lymphatic absorption contributed significantly to the overall insulin bioavailability following SC administration to sheep.     

Regional Gastrointestinal Absorption of Ranitidine in the Rat

Purpose. Ranitidine absorption from isolated segments of rat small intestine (duodenum, midgut, and terminal ileum) was investigated to examine the influence of pH and 50% bile, and to determine if ranitidine is absorbed preferentially from a specific region. Methods. Ranitidine (50 mg/kg) was administered into each segment in pH 5 or pH 7 buffer, or in 50% bile. Venous blood was collected at various times for 40 min from the right jugular vein. Results. When ranitidine was administered in pH 7 buffer or in 50% bile, C _max and AUC_0–40 were significantly greater after administration into the terminal ileum compared to the duodenum and midgut. AUC_0–40 was significantly greater when ranitidine was administered in pH 5 buffer or in 50% bile into the duodenum compared to the midgut. C _max was significantly different between administration into the duodenum and midgut only when ranitidine was administered in 50% bile. Ranitidine administration in pH 5 buffer significantly decreased AUC_{0– 40} and C _max after administration into the midgut, and AUC_0–40 after administration into the terminal ileum compared to administration with pH 7 buffer or in 50% bile. Bile had no significant effect on AUC_0–40 after ranitidine administration into the duodenum and midgut compared to administration in pH 7 buffer. However, bile significantly increased AUC_0–40and C _max after ranitidine administration into the terminal ileum compared to administration with pH 7 and pH 5 buffer. Conclusions. Results suggest that ranitidine is absorbed from the entire small intestine. However, the terminal ileum is the optimal site of gastrointestinal absorption. Furthermore, bile enhances ranitidine absorption from the terminal ileum.     

Daytime acid secretion after a single dose of ranitidine and cimetidine — a double blind crossover study

Summary The purpose of the study was to evaluate the duration of inhibition of acid secretion by single oral doses of cimetidine and ranitidine. Basal and postprandial acid secretion in 6 healthy volunteers were measured for 14 h by intermittent aspiration and prolonged intragastric titration. 400 mg cimetidine reduced daytime acid secretion by 22% and 150 mg ranitidine produced 38% inhibition. Although the elimination half lives of the drugs were similar, ranitidine led to more pronounced inhibition of acid secretion during the later part of the day. The longer duration of pronounced acid inhibition by ranitidine appears to be due solely to its greater potency.     

Theoretical Considerations on Two Equations for Estimating the Extent of Absorption After Oral Administration of Drugs

Purpose. The amount of drug absorbed into portal blood after oral dosing (D_p.o,g) has been estimated using Ficks principle (Q-method), i.e., D_p.o,g = Q_h · (AUC_p.o,g – AUC_p.o,c), where Q_h is the portal blood flow rate, and AUC_p.o,g and AUC_p.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate D_p.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; D_p.o,g = CL_S · AUC_p.o,g) is described using a simple pharmacokinetic model, to estimate D_p.o,g in the presence of systemic intestinal elimination, where CL_S is systemic clearance. Methods. The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating D_p.o,g was made using computer-simulation or experimental data of phenacetin from the literature. Results. The simulation study demonstrated that the Q-method underestimated D_p.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method,. The similar results were observed using the experimental data of phenacetin. Conclusions. The CL-method can provide a better estimate of D_p.o,g, while the Q-method may underestimate D_p.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.     

Pharmacokinetic Analysis of an Oral Sustained-Release Diltiazem Preparation Using Multifraction Absorption Models

Application of multifraction absorption models to pharmacokinetic analysis of an oral sustained-release diltiazem preparation (HER-SR) was investigated. The plasma diltiazem concentrations after oral administration of the HER-SR preparation were analyzed using both the two-fraction absorption model and the two-step discontinuous absorption model. The two-fraction absorption model was suitable for the pharmacokinetic analysis of the HER-SR preparation, whereas the two-step discontinuous absorption model is often unsuitable for the analysis of sustained-release preparations which disintegrate into fractions with different release characteristics in the gastrointestinal tract. The two-step discontinuous absorption model is usually not applicable to plasma concentration data when the first peak is sharp. MFA-MULTI(V) was shown to be useful for the prediction of the bioavailability in each fraction of HER-SR. It was further demonstrated that a two-fraction absorption model is useful for the comparison of in vitro and in vivo release profiles or evaluating the influence of food on the absorption behavior of HER-SR. In addition, the application of a two-fraction absorption model to population pharmacokinetics of HER-SR was investigated.     

Development and Validation of a Physiology-based Model for the Prediction of Oral Absorption in Monkeys

Purpose The development and validation of a physiology-based absorption model for orally administered drugs in monkeys is described. Materials and Methods Physiological parameters affecting intestinal transit and absorption of an orally administered drug in monkeys have been collected from the literature and implemented in a physiological model for passive absorption previously developed for rats and humans. Predicted fractions of dose absorbed have been compared to experimentally observed values for a set of N = 37 chemically diverse drugs. A sensitivity analysis was performed to assess the influence of various physiological model parameters on the predicted fraction dose absorbed. Results A Pearson’s correlation coefficient of 0.94 (95% confidence interval: [0.88, 0.97]; p < 0.0001) between the predicted and observed fraction dose absorbed in monkeys was obtained for compounds undergoing non-solubility limited passive absorption (N = 29). The sensitivity analysis revealed that the predictions of fractions dose absorbed in monkeys are very sensitive with respect to inter-individual variations of the small intestinal transit time. Conclusions The model is well suited to predict the fraction dose absorbed of passively absorbed compounds after oral administration and to assess the influence of inter-individual physiological variability on oral absorption in monkeys.     

Time-Dependent Oral Absorption Models

The plasma concentration–time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, k_a(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag time (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted C_max values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, k_a(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging from the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted C_max values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient k_a(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.     

Effects on cimetidine bioavailability of metoclopramide and antacids given two hours apart

Summary Plasma cimetidine levels were determined in 9 normal subjects after a single oral dose of cimetidine 400 mg under control conditions, 2 h before metoclopramide 20 mg and 2 h after a potent antacid. The bioavailability of cimetidine was not significantly affected by metoclopramide and it was marginally reduced by the antacid.     

Gastric pH Influences the Appearance of Double Peaks in the Plasma Concentration-Time Profiles of Cimetidine After Oral Administration in Dogs

The plasma concentration-time profiles of cimetidine often exhibit two peaks following oral administration of a single dose in the fasted state, while the concurrent administration of some antacids results in a lower extent as well as rate of absorption. In the present work, absorption of cimetidine after a single dose in the fasted state was studied as a function of gastric pH in male beagle dogs to determine whether gastric pH plays a role in the double peak phenomenon and/or can account for the decrease in bioavailability when antacids are coadministered. The extent of absorption of cimetidine was not influenced significantly by gastric pH, indicating that elevation of gastric pH is not the cause of decreases in the bioavailability of cimietidine when it is administered with antacids. Distinct double peaks or plateaux were noted in 8 of 10 plasma profiles when the gastric pH was 3 or below. Irregular absorption behavior was observed in 2 of 6 profiles in the pH range of 3 to 5, while single peaks were observed in all 10 profiles when the gastric pH was maintained at pH 5. It was concluded that gastric pH is a major factor in the generation of cimetidine double peaks. Changes in gastric pH also resulted in changes in the apparent kinetics of absorption. Below pH 5, absorption mostly followed zero-order kinetics (9 of 16 profiles) or a more complex kinetic process involving at least two components to the absorption phase (5 of 16 profiles). At gastric pH 5, however, absorption followed first order kinetics in 7 of 10 profiles. These differences in kinetics of absorption are postulated to arise from variations in gastric emptying as a function of pH and/or carryover effects of gastric pH into the upper intestine.