A general model of metabolite kinetics following intravenous and oral administration of the parent drug

A model of metabolite pharmacokinetics is developed in terms of residence time distributions and derived non-compartmental measures. It provides quantitative insight into factors determining the concentration-time curve of metabolite following intravenous and oral administration of the precursor drug. The AUCs and higher curve moments (mean residence times and relative dispersions) are calculated/predicted and their dependence on mean absorption time, fraction of first-pass metabolism and intrinsic disposition residence times of the parent drug and metabolite, respectively, is discussed. An AUC-based method for the determination of the first-pass effect is proposed which is not influenced by drug absorption. The approach is valid for linear pharmacokinetic systems exhibiting hepatic and renal elimination of the precursor drug; it is not restricted to specific compartmental models. Limitations of previous concepts of metabolite kinetics are defined. Criteria are presented for the appearance of concave metabolite curves in a semi-logarithmic scale.     

Determinants of systemic availability of promethazine in rabbits

Promethazine blood concentration-time curves have been determined in 7 rabbits following intravenous, oral and hepatic portal vein administration of promethazine. This phenothiazine has a large volume of distribution and a high metabolic clearance resulting in low blood concentrations particularly when the oral route is used. Analysis of the areas under the blood concentration-time curves indicates that hepatic first-pass metabolism is the major determinant of promethazine's low oral availability. Absorption from the gastrointestinal tract is essentially complete in most rabbits and the contribution of metabolism by the intestinal mucosa is minimal. The present findings are compared with the literature on other phenothiazines.     

A review of metabolite kinetics

The importance of metabolites as active and toxic entities in drug therapy evokes the need for an examination of metabolite kinetics after drug administration. In the present review, emphasis is placed on single-compartmental characteristics for a drug and its primary metabolites under linear kinetic conditions. The determination of the first-order elimination rate constants for drug and metabolite are also detailed. For any ith primary metabolite mi formed solely in liver, kinetic parameters with respect to primary metabolite formation under first-order conditions require a comparison of the areas under the metabolite concentration-time curve after drug and preformed metabolite administrations. These area ratios hold regardless of the number of noneliminating compartments for the drug and metabolite. These parameters include fmi and gmi, the fractions of total body clearance that respectively furnishes mi to the general circulation and forms mi, and hmi, the fraction of hepatic clearance responsible for the formation of mi. Moreover, the fraction of dose dmi converted to form mi is defined with respect to the route of drug administration. The inherent assumption of these estimates, however, requires that the extent of sequential elimination of the generated mi be identical to the extent of metabolism of preformed mi. Discrepancies have been found, and may be attributed mostly to the uneven distribution of drug-metabolizing activities as well as to the presence of diffusional barriers. Other linear systems that involve mi formation from multiple organs are briefly described.     

A review of metabolite kinetics

The importance of metabolites as active and toxic entities in drug therapy evokes the need for an examination of metabolite kinetics after drug administration. In the present review, emphasis is placed on single-compartmental characteristics for a drug and its primary metabolites under linear kinetic conditions. The determination of the first-order elimination rate constants for drug and metabolite are also detailed. For any ithprimary metabolite miformed solely in liver, kinetic parameters with respect to primary metabolite formation under first-order conditions require a comparison of the areas under the metabolite concentration-time curve after drug and preformed metabolite administrations. These area ratios hold regardless of the number of noneliminating compartments for the drug and metabolite. These parameters include f_mi and g_mi,the fractions of total body clearance that respectively furnishes mito the general circulation and forms mi,and h_mi,the fraction of hepatic clearance responsible for the formation of mi.Moreover, the fraction of dose d_mi converted to form miis defined with respect to the route of drug administration. The inherent assumption of these estimates, however, requires that the extent of sequential elimination of the generated mibe identical to the extent of metabolism of preformed mi.Discrepancies have been found, and may be attributed mostly to the uneven distribution of drug-metabolizing activities as well as to the presence of diffusional barriers. Other linear systems that involve miformation from multiple organs are briefly described.     

Primary, secondary, and tertiary metabolite kinetics

Because of the propensity of nascently formed metabolites towards sequential metabolism within formation organs, theoretical and experimental treatments that achieve mass conservation must recognize the various sources contributing to primary, secondary, and tertiary metabolite formation. A simple one-compartment open model, with first-order conditions and the liver as the only organ of drug disappearance and metabolite formation, was used to illustrate the metabolism of a drug to its primary, secondary, and tertiary metabolites, encompassing the cascading effects of sequential metabolism. The concentration-time profiles of the drug and metabolites were examined for two routes of drug administration, oral and intravenous. Formation of the primary metabolite from drug in the gut lumen, with or without further absorption, and metabolite formation arising from first-pass metabolism of the drug and the primary metabolite during oral absorption were considered. Mass balance equations, incorporating modifications of the various absorption and conversion rate constants, were integrated to provide the explicit solutions. Simulations, with and without consideration of the sources of metabolite formation other than from its immediate precursor, were used to illustrate the expected differences in circulating metabolite concentrations. However, a simple relationship between the area under the curve of any metabolite, M, or [AUC (m)], its clearance [CL(m)], and route of drug administration was found. The drug dose, route, fraction absorbed into the portal circulation, Fabs, fraction available of drug from the liver, F, availabilities of the metabolites F(m) from formation organs, and CL(m) are determinants of the AUC(m)'s. After iv drug dosing, the area of any intermediary metabolites is determined by the iv drug dose divided by the (CL(m)/F(m] of that metabolite. When a terminal metabolite is not metabolized, its area under the curve becomes the iv dose of drug divided by the clearance of the terminal metabolite since the available fraction for this metabolite is unity. Similarly, after oral drug administration, when loss of drug in the gut lumen does not contribute to the appearance of metabolites systematically, the general solution for AUC(m) is the product of Fabs and oral drug dose divided by [CL(m)/F(m)]. A comparison of the area ratios of any metabolite after po and iv drug dosing, therefore, furnishes Fabs. When this fraction is divided into the overall systemic availability or Fsys, the drug availability from the first-pass organs, F, may be found.(ABSTRACT TRUNCATED AT 400 WORDS)     

Simultaneous pharmacokinetic modeling of cocaine and its metabolites, norcocaine and benzoylecgonine, after intravenous and oral administration in rats.

To accurately assess the mechanism of involvement of the active metabolite norcocaine in the effects of oral cocaine, it is essential to determine the rate and extent of the formation of norcocaine. Although this study was designed specifically for this aim, it was also of interest to characterize the metabolite kinetics of benzoylecgonine for comparative purpose. We first characterized the pharmacokinetics of cocaine, norcocaine, and benzoylecgonine by the i.v. route of administration; all three drugs decayed biexponentially. These pharmacokinetic estimates were then used for determination of the formation of norcocaine and benzoylecgonine after i.v. and p.o. (20-40 mg/kg) cocaine administration. Although t(1/2alpha), and t(1/2beta) were similar across the three compounds, the values of volume of distribution in the central compartment and clearance for benzoylecgonine were much smaller than those of cocaine and norcocaine. Norcocaine was not detected following i.v. cocaine; however, serum norcocaine concentrations were as high as those of oral cocaine. Both routes of cocaine administration produced benzoylecgonine. A pharmacokinetic model for the metabolite kinetics was proposed by sequentially adding the models that most adequately described the formation of each metabolite to the model of cocaine. For oral cocaine, the absolute bioavailability was 3.48%, whereas 6.04 and 2.26% of cocaine were converted to benzoylecgonine and norcocaine, respectively, during first-pass absorption regardless of dose. Furthermore, the majority of norcocaine and 92% of benzoylecgonine were formed during the first-pass absorption, leaving 8% of benzoylecgonine produced in systemic circulation. The profile of norcocaine as a metabolite confirmed the involvement of norcocaine in cocaine's behavioral effects.     

Pharmacokinetic interaction between verapamil and metoprolol in the dog. Stereochemical aspects.

The effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium-labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first-pass effect of metoprolol was completely abolished after co-administration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 +/- 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil co-administration (R/S ratio = 1.01 +/- 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil co-administration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.     

Primary,secondary, and tertiary metabolite kinetics

Because of the propensity of nascently formed metabolites towards sequential metabolism within formation organs, theoretical and experimental treatments that achieve mass conservation must recognize the various sources contributing to primary, secondary, and tertiary metabolite formation. A simple one-compartment open model, with first-order conditions and the liver as the only organ of drug disappearance and metabolite formation, was used to illustrate the metabolism of a drug to its primary, secondary, and tertiary metabolites, encompassing the cascading effects of sequential metabolism. The concentration-time profiles of the drug and metabolites were examined for two routes of drug administration, oral and intravenous. Formation of the primary metabolite from drug in the gut lumen, with or without further absorption, and metabolite formation arising from first-pass metabolism of the drug and the primary metabolite during oral absorption were considered. Mass balance equations, incorporating modifications of the various absorption and conversion rate constants, were integrated to provide the explicit solutions. Simulations, with and without consideration of the sources of metabolite formation other than from its immediate precursor, were used to illustrate the expected differences in circulating metabolite concentrations. However, a simple relationship between the area under the curve of any metabolite, M,or [AUC{m}],its clearance [CL{m}],and route of drug administration was found. The drug dose, route, fraction absorbed into the portal circulation, F_abc,fraction available of drug from the liver, F,availabilities of the metabolites F{m}from formation organs, and CL{m}are determinants of the AUC{m}'s.After iv drug dosing, the area of any intermediary metabolites is determined by the iv drug dose divided by the (CL{m}/F{m})of that metabolite. When a terminal metabolite is not metabolized,its area under the curve becomes the iv dose of drug divided by the clearance of the terminal metabolite since the available fraction for this metabolite is unity. Similarly, after oral drug administration, when loss of drug in the gut lumen does not contribute to the appearance of metabolites systemically, the general solution for AUC{m} isthe product of F_abc and oral drug dose divided by [CL{m}/F{m}].A comparison of the area ratios of any metabolite after po and iv drug dosing, therefore, furnishes F_abc.When this fraction is divided into the overall systemic availability or F_sys,the drug availability from the first-pass organs, F,may be found. The potential application of these relationships to other schemes, namely, drugs that have competing metabolic pathways within the liver and/or intestine as well as reversible metabolism is briefly discussed.In view of the various contributing sources of metabolite formation, and the modulation of circulating metabolite concentrations by sequential first-pass metabolism of the metabolite, caution is given against the use of area ratios of metabolite after iv drug and metabolite administration for estimations of metabolite formation clearances.This work was supported by the Medical Research Council of Canada (MA-9104 and MA-9765) and the NIH (GM-38250). KSP is a recipient of the Faculty Development Award from MRC, Canada.     

Acute hepatic damage in rats impairs metharbital metabolism

Metharbital metabolism was impaired in rats after acute hepatic damage induced by carbon tetrachloride. Compared to control rats, hepatic damage prolonged the metharbital sleeping time and reduced the slopes of log metharbital plasma concentration-time curves. Renal contributions to metharbital elimination from plasma were negligible since only about 6% of the metharbital administered was eliminated unchanged in urine. In rats with hepatic damage, metharbital clearance from plasma and elimination of its demethylated metabolite, barbital, in urine decreased with increasing severity of damage. These results indicate that the kinetics of both metharbital and its metabolite reflect sensitively hepatic drug-metabolizing capacity. Measuring urinary elimination of barbital, following metharbital administration, may serve as a convenient laboratory test to evaluate the hepatic drug-metabolizing capacity.     

Clinical significance of pharmacokinetic models of hepatic elimination

Various pharmacokinetic models, both simple and complex, have been developed to describe the way in which the rate of hepatic elimination of drugs depends on hepatic blood flow, hepatic intrinsic clearance and unbound fraction of drug in blood. A model is necessary because it is not possible to measure the average blood concentration of drug within the liver, i.e. the concentration at the site of drug elimination. However, the predictions of these models can differ markedly for drugs of high hepatic clearance, especially with the oral route of administration. Investigations of the models have mostly involved studies with in vitro experimental preparations, such as isolated perfused livers. While such studies have advanced our understanding of the mechanism of hepatic uptake and elimination processes, the implications for clinical drug usage have been somewhat neglected. Use of one of the available models is necessary for the assessment of the capacity of in vivo hepatic drug metabolism processes (i.e. hepatic intrinsic clearance) and for predicting the effect of increasing dose on blood concentrations of high clearance drugs exhibiting Michaelis-Menten elimination kinetics, especially those that undergo a nonlinear hepatic first-pass effect. Clinically significant differences between the models can occur under these circumstances. A model is also required for quantitative prediction of the effect on blood drug concentrations of changes in hepatic blood flow, hepatic intrinsic clearance or drug-protein binding in blood. It is in predicting these changes that differences of major clinical significance can occur between the models. The greatest differences are seen in predicting the effect for orally administered drugs of changes of hepatic blood flow on blood concentrations, and changes of protein binding on unbound blood concentrations of drug. These changes can result from disease processes, altered physiology (old age or pregnancy), food intake or concomitant administration of other drugs. A model is also required for determining the mechanism by which such clinical changes occur. When considering these effects on hepatic elimination, it is essential to appreciate that the conclusions may depend markedly on the particular model chosen. Until more data on the applicability of the models are obtained in humans, the undistributed sinusoidal and venous equilibrium models, which represent the opposite extremes of behaviour among the available models, should both be used in assessing hepatic drug elimination.     

Simultaneous determination of the intravenous and oral pharmacokinetic parameters of D,L-verapamil using stable isotope-labelled verapamil

Summary Following i. v. administration, the plasma concentration-time curve of verapamil could best be described by either a mono- or biexponential equation. Total plasma clearance (1.26 l/min) approached liver blood flow (1.5 l/min), so it can be concluded that its clearance is liver blood flow-dependent. Although absorption was almost complete after oral administration, absolute bioavailability (20%) was low, due to extensive hepatic first-pass metabolism. The approach using stable isotope-labelled and unlabelled drug permits simultaneous administration by the intravascular and extravascular routes, thus allowing determination of absolute bioavailability in a single experiment.     

Influence of renal failure on the hepatic clearance of bufuralol in man

The beta-blocking agent bufuralol is subject to first-pass metabolism and is eliminated from the body almost entirely by biotransformation. Its major metabolite in plasma (1'-hydroxy-bufuralol) is biologically active and may contribute to the pharmacological effect of the drug. The effect of renal failure on the behavior of the parent compound and three of its metabolites was studied by comparing their kinetics in normal volunteers and in patients with severe renal insufficiency. Bufuralol was given orally to all subjects (20 mg); some of the healthy volunteers also received the drug intravenously (5 mg). Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent compound, whereas its halflife of elimination was not markedly influenced. The behavior of 1'-hydroxy-bufuralol was consistent with a decreased renal clearance. The behavior of bufuralol in patients with renal failure was analyzed using the clearance approach. From this analysis it appears that the presystemic biotransformation of bufuralol is decreased in renal failure and that changes in systemic clearance are compensated in our patients by modifications of the volume of distribution, resulting in little net change in the halflife of elimination.     

First-pass metabolism of decursin, a bioactive compound of Angelica gigas, in rats

Decursin is considered the major bioactive compound of Angelica gigas roots, a popular Oriental herb and dietary supplement. In this study, the pharmacokinetics of decursin and its active metabolite, decursinol, were evaluated after the administration of decursin in rats. The plasma concentration of decursin decreased rapidly, with an initial half-life of 0.05 h. It was not detectable at 1 h after intravenous administration at an area under the plasma concentration-time curve of 1.20 μg · mL-1·h, whereas the concentration of decursinol increased rapidly reaching a maximum concentration of 2.48 μg · mL-1 at the time to maximum plasma concentration of 0.25 h and an area under the plasma concentration-time curve of 5.23 μg · mL-1·h. Interestingly, after oral administration of decursin, only decursinol was present in plasma, suggesting an extensive hepatic first-pass metabolism of decursin. The extremely low bioavailability of decursin after its administration via the hepatic portal vein (the fraction of dose escaping first-pass elimination in the liver, FH = 0.11) is indicative of extensive hepatic first-pass metabolism of decursin, which was confirmed by a tissue distribution study. These findings suggest that decursin is not directly associated with the bioactivity of A.?gigas and that it may work as a type of natural prodrug of decursinol.     

Pharmacokinetics of tetrabenazine and its major metabolite in man and rat. Bioavailability and dose dependency studies

The pharmacokinetics of tetrabenazine (TBZ), a catecholamine and serotonin depletor, and its major metabolite, dihydrotetrabenazine (HTBZ), were studied in four patients affected by tardive dyskinesia, who were under treatment with different doses of TBZ (12.5-37.5 mg, t.i.d.), and in the rat. In the patients, the steady-state area under the plasma concentration-time curves (AUCs) of the metabolite were 82.6-199-fold higher than those of TBZ. The drug showed a small and erratic bioavailability (F = 0.06 +/- 0.026, mean +/- SD). It appears to be extensively metabolized, as no unchanged TBZ could be detected in the urine of the patients. Single oral doses of 0.5-10 mg/kg and single iv dose of 1 mg/kg of TBZ were each administered to four to six rats. The clearance of the drug following iv administration to the rat (mean +/- SD, 58.9 +/- 6.01 ml X min-1 X kg-1) was very close to the rat hepatic blood flow indicating a perfusion-limited clearance. An F value of 0.17 was obtained following iv and po doses of 1 mg/kg TBZ in the rat. The oral absorption of TBZ seems to be rapid and almost complete. Plots of the AUCs of TBZ and HTBZ vs. five different po doses (0.5-10 mg/kg) were linear with correlation coefficients of 0.998 and 0.986 for TBZ and HTBZ, respectively, suggesting linear kinetics in the examined dosage range. In both the patients and rats, the plasma profile of TBZ followed characteristics of a multiexponential pharmacokinetic model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-dependent presystemic elimination of propranolol due to hepatic first-pass metabolism in rats

Gastrointestinal first-pass elimination of propranolol and the effect of dose (1.0, 2.5, 5.0 and 10.0 mg kg-1) on its systemic availability were studied in male Wistar rats which received the drug intravenously, orally or intraportally. The plasma elimination half-life was not altered either by the route of administration or the dose. There was no gastrointestinal first-pass metabolism of propranolol, since the same systemic availability was obtained after oral and intraportal administration. Hepatic clearance was estimated to be constant at any dose. In contrast, the hepatic intrinsic clearance was found to be largely dependent on the portal dose.     

Cocaethylene formation following ethanol and cocaine administration by different routes

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d?) was administered in all conditions. Oral cocaine-d? 2.0 mg/kg, intravenous cocaine-d? 1.0 mg/kg, and smoked cocaine-d? (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d?) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d?, cocaethylene-d?, cocaethylene-d?, and benzoylecgonine-d? were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs.     

Effects of First-Pass Metabolism on Metabolite Mean Residence Time Determination After Oral Administration of Parent Drug

Metabolite kinetics after oral drug administration can be determined, without separate metabolite administration, using the concepts of mean residence time (MRT). The MRT of parent drug and metabolite after oral administration of the parent drug, MRTp,p(oral) and MRTm,p(oral), can be calculated directly from the drug and metabolite profiles. The difference between MRTm,p(oral) and MRTp,p(oral), termed Delta MRT, yields an estimate of MRT of metabolite when the metabolite is given as an iv bolus, MRTm,m(iv). The calculation is simple for drugs that are known to undergo negligible first-pass metabolism. Correction can also be made when extent of first-pass metabolism is known. Ambiguity is encountered, however, when the degree of first-pass metabolism is unknown. When the delta MRT is negative, then first-pass metabolism must be considered. A positive value of delta MRT, on the other hand, is not a definitive indication of the absence of first-pass metabolism. It may occur in the presence or absence of first-pass metabolism. Ignoring the possibility of first-pass metabolism when a positive value of delta MRT occurs may lead to an incorrect estimate of MRTm, m(iv). The estimation error is relatively small, however, when MRTm,m(iv) MRTp,p(iv), even when first-pass metabolism is extensive. This situation may apply to the administration of a prodrug.     

Plasma propranolol concentrations in rats with adjuvant-induced arthritis

Previous work has shown that after a single oral dose, plasma propranolol concentrations in patients with active inflammatory disease are significantly higher than those in healthy subjects. After oral administration of propranolol (2 mg) to arthritic rats, the area under the mean drug concentration-time curve in plasma was approximately 10 times greater than that in control animals. After intravenous administration (0.25 mg) the area in arthritic rats was approximately doubled compared with that in controls. The mechanisms causing these changes are not known, but it is probable that increased drug binding to an acute phase reactant in plasma, together with decreased first-pass hepatic clearance in arthritic rats after oral dosing, are involved.     

Cyclosporin-erythromycin interaction in normal subjects.

We studied the pharmacokinetic interaction between cyclosporin (CYA) and erythromycin in normal subjects. Plasma CYA concentrations were measured by high performance liquid chromatography (h.p.l.c.) and radioimmunoassay (RIA) and estimates of metabolite formation were obtained from inter-assay differences between these measurements. Erythromycin significantly increased the maximum concentration and the area under concentration-time curve. Time to maximum concentration and apparent oral clearance of CYA were significantly decreased. The half-life, however, was not altered. Significant reductions in the proportion of apparent metabolite were observed at times of maximum CYA concentrations but not at later time periods (12 and 24 h). The mechanism of the drug interaction appears to be decreased hepatic first-pass metabolism but an effect on CYA absorption cannot be excluded. These results on normal subjects confirm that patients administered CYA and erythromycin risk CYA toxicity. However, the risk can be reduced by dose reduction based on more frequent CYA monitoring or by using a different antibiotic.     

Bioavailabilities of omeprazole administered to rats through various routes

Omeprazole, a proton pump inhibitor, was given intravenously (iv), orally (po), intraperitoneally (ip), hepatoportalvenously (pv), and intrarectally (ir) to rats at a dose of 72mg/kg in order to investigate the bioavailability of the drug. The extent of bioavailabilities of omeprazole administered through pv, ip, po, and ir routes were 88.5, 79.4, 40.8, and 38.7%, respectively. Pharmacokinetic analysis in this study and literatures (Regardhet al., 1985: Watanabeet al., 1994) implied significant dose-dependency in hepatic first-pass metabolism, clearance and distribution, and acidic degradation in gastric fluid. The high bioavailability from the pv administration (88.5%) means that only 11.5% of dose was extracted by the first-pass metabolism through the liver at this dose (72 mg/kg). The low bioavailability from the oral administration (40.8%) in spite of minor hepatic first-pass extraction indicates low transport of the drug from GI lumen to portal vein. From the literature (Pilbrant and Cederberg, 1985), acidic degradation in gastric fluid was considered to be the major cause of the low transport. Thus, enteric coating of oral preparations would enhance the oral bioavailability substantially. The bioavailability of the drug from the rectal route, in which acidic degradation and hepatic first-pass metabolism may not occur, was low (38.7%) but comparable to that from the oral route (40.8%) indicating poor transport across the rectal membrane. In this case, addition of an appropriate absorption enhancer would improve the bioavailability. Rectal route seems to be an possible alternative to the conventional oral route for omeprazole administration.