Evaluation of Intestinal Absorption into the Portal System in Enterohepatic Circulation by Measuring the Difference in Portal–Venous Blood Concentrations of Diclofenac

Purpose. We evaluated the first-pass effects in vivo by the intestine and liver during enterohepatic circulation (EHC) by simultaneously measuring the portal and venous plasma concentrations of the rat. Methods. The venous and upper portal blood vessels were cannulated through the jugular and the pyloric veins, respectively, to obtain simultaneously blood samples from both sites. After diclofenac was injected as a bolus through the jugular vein, the concentrations of diclofenac in the portal and jugular veins were measured at time intervals. The absorption rate from the intestinal tract into the portal system was determined using the portal–venous difference in plasma concentrations of diclofenac, considering 40% partitioning of diclofenac into erythrocytes. Results. After one hour, the plasma concentration in the portal vein was always higher than that in the jugular vein in awakening rats with intact EHC (portal–venous blood concentration difference). No portal–venous difference was observed in awakening rats with bile-duct cannulation. Therefore, it was concluded that this portal–venous concentration difference was not due to the hepatic clearance but to diclofenac reabsorption from the intestinal tract. Conclusions. Appropriately 40% of the dose of diclofenac was reabsorbed over 8 hours from the intestinal tract into the portal system. By comparing the reabsorbed amounts in the portal system and in the systemic circulation, the hepatic extraction ratio in vivo (F_H) of diclofenac was estimated to be 63%.     

Method to Estimate the Rate and Extent of Intestinal Absorption in Conscious Rats Using an Absorption Probe and Portal Blood Sampling

Purpose. A variety of methods exist which determine the rate and extent of intestinal absorption. The method described here employs an internal absorption reference probe and portal blood sampling in unanesthetized rat. Methods. Theophylline and tritiated water were selected as absorption reference probes since they are quantitatively absorbed in conscious rat. The fraction of an intestinal dose which reaches portal blood was determined from the resulting portal-systemic blood concentration gradients of the drug relative to the absorption probe. The absorption probes provide a means to calculate the drug mass reaching portal blood without the need of measuring the portal blood flow rate. The technique was evaluated with verapamil and a well-absorbed 5-lipoxygenase inhibitor, A-79035. Results. The fraction of an intrajejunal dose of A-79035 reaching the portal vein (F_G) was 0.86 using theophylline as the absorption probe. Verapamil, which is susceptible to extensive hepatic first-pass elimination, was completely absorbed (F_G = 0.98) within 1 hour, but was only 21.4% bioavailable. Absorption rate constants, estimated from initial appearance rates in portal blood, were used to monitor factors that affect drug absorption. For example, with a dose solution containing 30% PEG-400, the absorption rate constants of theophylline and A-79035 were significantly reduced. Anesthesia reduced the absorption rate constant for theophylline in rats by 40% compared to conscious animals. Conclusions. The technique detailed here allows reliable, direct measurement of intestinal absorption which may assist in characterizing oral dosing for novel therapeutic agents.     

Evaluation of absorbability of centpropazine in rats: in-situ and in-vivo appraoches.

Intestinal absorption of centpropazine was studied in rats by both in-situ (closed-loop method) and in-vivo (portal-venous difference) approaches. The drug was found to be well absorbed from solution in in-situ studies. However, the results obtained in-vivo suggested that very low amounts of drug reach the portal circulation after oral dosing. This could imply extensive binding to the mucosa or metabolism in the intestinal wall. The presence of higher amounts of metabolites in the portal vein compared with the inferior vena cava samples signal their formation in the gastrointestinal tract or enterohepatic recirculation. These findings will be useful in incorporating suitable structural and formulation modifications for enhancing the bioavailability of centpropazine and its analogues.     

The Effect of Blood Sampling Site and Physicochemical Characteristics of Drugs on Bioavailability After Nasal Administration in the Sheep Model

Purpose. Investigate the effect of blood sampling site and physicochemical characteristics of drugs on the pharmacokinetic (PK) parameters obtained after intravenous and nasal administration in sheep and compare results with computer simulations. Methods. Three drugs, insulin, morphine, and nicotine, were administered nasally and by intravenous (IV) injection to sheep, and serial blood samples collected concurrently from the carotid artery (insulin, morphine) or cephalic vein (nicotine) and jugular vein. Plasma drug concentrations were measured, and pharmacokinetic and statistical analyses performed, to evaluate sampling site differences. Results. After nasal insulin, bioavailabilities calculated from the two blood sampling site data were comparable. In contrast, apparent bioavailabilities following nasal morphine or nicotine were significantly higher when sampling was from the jugular vein. These results were supported by computer simulations. These observations are attributed to the greater effects of noninstantaneous mixing of drugs for jugular vein sampling following nasal dosing, compared to the other sampling sites, which is significant for drugs that are rapidly and well absorbed and that have a high volume of distribution (V_d). Conclusion. The results clearly show that the characteristics of the drug and the blood sampling site can have a significant effect on the pharmacokinetic results obtained after nasal administration in sheep.     

Stereoselective pharmacokinetics of BOF-4272 racemate after oral administration to rats and dogs

The stereoselective pharmacokinetics of BOF-4272 enantiomers in rats and dogs was investigated by simultaneously measuring concentrations in arterial, portal, and venous plasma, the liver, and the kidney at 2 h after the oral administration of the racemic drug. The concentrations of BOF-4272 enantiomers were measured using high-performance liquid chromatography. The concentrations of the S(-) enantiomer in arterial, portal, and venous plasma were higher than those of the R(+) enantiomer in rats, but the opposite was found in dogs. In rats, absorption from the intestinal tract into the portal system was almost the same for the two enantiomers, whereas the hepatic uptake of the R(+) enantiomer was greater than that of the S(-) enantiomer. In dogs, absorption from the intestinal tract into the portal system was greater for the R(+) enantiomer than for the S(-) enantiomer, whereas hepatic uptake was comparable for the two enantiomers. The stereoselectivity of the renal uptake of BOF-4272 enantiomers had little effect on the stereoselectivity of enantiomers in the systemic circulation in both rats and dogs. The stereoselectivity in the systemic circulation of BOF-4272 enantiomers is therefore related to hepatic uptake in rats, and to absorption from the intestinal tract into the portal system in dogs.     

Separate assessment of intestinal and hepatic first-pass effects using a rat model with double cannulation of the portal and jugular veins

To separately assess intestinal and hepatic first-pass effects with absorption ratio data, we have established an experimental model of rats double-cannulated into the portal and jugular veins. The model allows us to take blood samples simultaneously from conscious rats that have recovered from surgical damage. Double cannulation did not alter the physiological and hematological conditions. Moreover, the plasma concentration profiles of unchanged drug following oral and intravenous administration in the double-cannulated rats were not different from those of rats single-cannulated into the jugular vein. These results suggest that the model can be useful for separately assessing intestinal and hepatic first-pass effects.We evaluated the first-pass effects in the intestine and the liver separately using this model. S-1452, as a model drug with 94% absorption ratio, was administered intravenously and orally to the double-cannulated rats, and the drug concentrations in the portal and systemic plasma were determined, and the rates of elimination from the intestine and liver were estimated. In the first pass, approximately 26% and 56% of the dose were extracted by the intestine and liver, respectively.This method, in which the animal is not restricted nor under anesthesia, allows us to obtain reliable values of individual first pass effects in the intestine and liver. This method can also be an effective tool for assessing the site and extent of drug-drug interaction on the first-pass effects.     

Differentiation of Gut and Hepatic First-Pass Effect of Drugs: 1. Studies of Verapamil in Ported Dogs

Purpose. To investigate the relative contributions of the gut and liver to the first-pass loss of verapamil (VL) using anin vivo intestinal-vascular access port (IVAP) dog model. Methods. Basic pharmacokinetics of VL were determined after intravenous (IV: 0.5 mg/kg), portal venous (PV: 2 mg/kg), and duodenal (ID: 2 mg/kg) administration in IVAP dogs. Serial blood samples were collected for 8 h after dosing, and plasma was analyzed for unchanged drug by a high-performance liquid chromatography-fluorescence method. Extraction ratios in the liver and intestinal tract were determined from the area under the concentration-time curves for ID, PV, and IV administration. The functional role of CYP450 or secretory transporters such as P-gp on the gut and liver first-pass loss of VL was further studied using ritonavir, a known substrate or inhibitor of these processes. Results. The liver had a high intrinsic capacity for clearing VL because the absolute bioavailability (BA) of VL was 21.7% after PV administration. The BA of VL after ID administration was 23.5%; therefore, intestinal absorption was complete and intestinal extraction was negligible (ER_GI 0). The BA of VL increased from 23.5% to 66.2% in the presence of ritonavir primarily due to a reduction in hepatic extraction. Conclusions. Although the liver had a high intrinsic capacity for extracting VL, the contribution of gut to the first-pass loss of VL was negligible. Because of the additive effects of intestinal CYP3A-mediated metabolism and secretory transport, a significant gut first-pass effect was expected, but not observed in dogs. These studies demonstrate the utility of the in vivo IVAP dog model for evaluating the relative contribution of the gut and liver to the first-pass loss of drugs and for characterizing the functional role that CYP450 metabolism and/or secretory transporters play in drug-drug interactions and reduced oral bioavailability.     

Intestinal absorption and secretion of ochratoxin A in the rat

The absorption and secretion of ochratoxin A (OA) by the gastrointestinal tract were studied in the rat. When OA was introduced into the lumen at various sites of the gastrointestinal tract, the largest concentration of OA in portal blood was found after the toxin was injected into the lumen at the proximal jejunum. After the injection of OA into a closed loop at the proximal jejunum, the rate of appearance of OA in the mesenteric venous plasma was higher than that in lymph. The rate of appearance in the venous plasma increased with an increase in the luminal concentration of OA while in the lymph the rate remained almost constant with respect to the luminal OA concentration. These results suggest that the site of maximal absorption is the proximal jejunum and that the primary route of absorption is the portal vein although the contribution of the lymphatic route cannot be excluded when low-dose levels of OA are given. When various parts of the gastrointestinal tract were perfused after iv injection of OA, noticeable amounts of the toxin appeared in the intestinal perfusate, suggesting that intestinal secretion may be another route of excretion of OA. Comparison of intestinal secretion and absorption showed asymmetric transfer of OA across the intestinal mucosa, the lumen-to-blood transfer being greater than that in the opposite direction.     

Mechanism of Compound- and Species-Specific Food Effects of Structurally Related Antiarrhythmic Drugs,Disopyramide and Bidisomide

Purpose. To determine mechanism of food effects observed with bidisomide but not with the structurally similar drug, disopyramide. Methods. Food effect studies of bidisomide and disopyramide were conducted with and without a standardized high fat meal in healthy subjects and in the dog. Intestinal metabolism of disopyramide and absorption of the metabolites were examined after oral administration of the drug to the dogs with portal vein canula implanted. Effects of food or a mixture of amino acids on metabolism of [¹⁴C]disopyramide were examined after intraportal infusion of the drug with and without high fat meal and after drug infusion into portal vein with the amino acid mixture, respectively. Results. The systemic availability of bidisomide was markedly reduced with food in humans, whereas the systemic availability of disopyramide did not change notably. In the dog, the systemic availability of bidisomide was also reduced with food. The systemic availability of disopyramide did not change with food. This was due to the fact that reduction in absorption was compensated by reduction of metabolism. There was no evidence for reduction in hepatic and intestinal metabolism with food. Conclusions. The apparent reduction in disopyramide metabolism with food may be due to an increase in colonal and /or lymphatic absorption. Food effects on the apparent systemic availability of bidisomide and disopyramide in the dog were similar to those in the rat. However, there was substantial species difference in the mechanism of food effects.     

A recirculatory model for local absorption and disposition of ciprofloxacin by measuring portal and systemic blood concentration difference.

A recirculatory model for the portal-systemic blood concentration difference (P-S difference) was developed to separately evaluate the rate and extent of absorption from the gastrointestinal tract into the portal system and disposition of a drug in the body. To apply this model to pharmacokinetic analysis, ciprofloxacin was selected as a model drug possessing a moderate intestinal absorption, and renal and hepatic elimination. The portal and systemic blood samples were simultaneously taken from rats at appropriate time points after intravenous and oral administration of ciprofloxacin at a dose of 5 mg/kg. After intravenous administration, little or no difference in the concentrations between the portal and systemic blood was observed, whereas after oral administration the concentrations of ciprofloxacin in the portal blood were consistently higher than those in the systemic blood over the time studied. This difference observed after oral administration is attributed to the absorption of ciprofloxacin from the gastrointestinal tract into the portal system. On the basis of the moment analysis deduced from the recirculatory model, the portal blood flow rate (Q(p)), the local absorption ratio from the gastrointestinal tract into the portal system (F(a)), the hepatic recovery ratio (F(h)), and bioavailability (BA) were then estimated. The obtained Q(p) of 2.81 L/h/kg, F(a) of 32.6, F(h) of 68.1, and BA of 22.2% were found to be in good agreement with the reported values. Furthermore, the mean local absorption time from the gastrointestinal tract into the portal system (t(a)) calculated by a nonlinear least-squares program [MULTI (FILT)] was almost identical with that by the global moments. These results suggest that the model proposed in this study would be useful for evaluating both in vivo absorption and disposition of drugs.     

Intestinal Transport of Gentamicin with a Novel,Glycosteroid Drug Transport Agent

Purpose. The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. Methods. Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. ³H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. Results. The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal or jejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. Conclusions. TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.     

Gastrointestinal first-pass effect of furosemide in rats

The first-pass effect of furosemide was investigated in rats. Furosemide intravenous solution (20 mg kg(-1) Lasix), was administered via the jugular vein and the portal vein, orally, and instilled directly into the duodenum of rats. The first-pass effects of furosemide by lung, heart, and liver seemed to be negligible in rats. The absolute bioavailability of furosemide was 28.9 and 48.3% after oral and intraduodenal administration, respectively. Based on the gastrointestinal (GI) recovery study, 68.3 and 69.5% of furosemide were found to have disappeared mainly due to absorption and/or metabolism from rat GI tract after oral and intraduodenal administration, respectively. The results indicate that gastrointestinal and intestinal first-pass effects of furosemide were approximately 40% (68.3-28.9%) and 20% (69.5-48.3%) of the dose, respectively.     

The impact of the site of blood sampling on pharmacokinetic parameters following sublingual dosing to dogs

IntroductionDrugs are most commonly administered orally, but some potential drug candidates are not suited for oral administration due to poor absorption, high first pass metabolism or gastrointestinal side effects. The interest for transmucosal dosing for systemic drug delivery is increasing, e.g. buccal, sublingual and nasal routes. The evaluation of the systemic plasma concentration and the derivation of the pharmacokinetic parameters of candidate compounds in preclinical studies are essential for drug development. The effect of site of blood sampling on the measured drug concentration, in both animals and humans, is to some extent known but it is not always taken into consideration in the design of pharmacological and toxicological studies.MethodsBlood samples were collected both from leg and jugular veins from beagle dogs following a single sublingual dosing of Compound A in order to determine the impact of different sites of blood sampling on plasma pharmacokinetics. Plasma was prepared by centrifugation and plasma concentrations of Compound A were determined by protein precipitation and liquid chromatography followed by mass spectrometric detection. The pharmacokinetic parameters were calculated by non-compartment methods.ResultsSampling from the jugular vein resulted in higher and more variable exposure during the absorption phase compared to sampling from a leg vein. The plasma exposure in the jugular vein, in terms of C_max, was 4-fold compared to that in the leg vein and an approximately 2-fold bioavailability was observed.DiscussionThe aim of this investigation was to determine the impact of the different sites of blood sampling on assessing systemic plasma exposure and pharmacokinetic parameters for Compound A following sublingual dosing to dogs. The results demonstrate the significant impact that the site of blood sampling has on PK parameters, and raise concerns of using the jugular vein as a site of sampling after sublingual and other transmucosal routes of dosing in the head region.     

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine

Purpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and C_max parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.     

超声下两种颈内静脉置管法的比较

目的 超声下比较两种路径颈内静脉置管方法的准确性及并发症的发生率,寻找更安全、可靠的颈内静脉穿刺路径。方法 选择需行颈内静脉穿刺患者60例,随机分为传统中路法穿刺组(A组,n=30)与颈内静脉搏动点法穿刺组(B组,n=30)。观察颈总动脉直径(D1)、颈内静脉直径(D2)、颈总动脉和颈内静脉重叠覆盖率、穿刺路径距颈内静脉中心距离(D3)、穿刺路径距颈总动脉外侧距离(D4)及可能触及颈总动脉例数。结果 与A组比较,B组D3较小,差异有统计学意义(P<0.05);B组D4明显大于A组,差异有统计学意义(P<0.05)。结论 颈内静脉搏动点法行颈内静脉穿刺更准确,并发症发生率更低。     

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.     

Impact of Mrp2 on the Biliary Excretion and Intestinal Absorption of Furosemide,Probenecid, and Methotrexate Using Eisai Hyperbilirubinemic Rats

Purpose. This study assesses the impact of rat multidrug resistance-associated protein 2 (Mrp2) on the biliary excretion and oral absorption of furosemide, probenecid, and methotrexate using Eisai hyperbilirubinemic rats (EHBR). Methods. To assess Mrp2-mediated biliary excretion, rats received a 2-h intravenous infusion of furosemide, probenecid, or methotrexate. Blood and bile samples were collected at specified intervals. To assess Mrp2's impact on oral absorption, rats received furosemide, probenecid, or methotrexate orally at 5 mg/kg. Jugular and portal blood samples were obtained at timed intervals. All samples were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated using WinNonlin and standard pharmacokinetic equations. Results. Thirty seven- and 39-fold reductions in biliary clearance were observed in EHBR as compared to control rats for probenecid and methotrexate, respectively. Biliary clearance was comparable between EHBR and control rats for furosemide. In all cases, no significant difference in absorption was observed between EHBR and control rats. Conclusions. This study provides the first evidence that Mrp2 mediates the biliary excretion of probenecid but not furosemide. Additionally, Mrp2 apparently has a less profound impact on intestinal absorption than biliary excretion of its substrates. Furthermore, alteration in systemic clearance in EHBR indicates that a potential compensatory mechanism may occur in EHBR.     

Some aspects of the intestinal absorption of zinc in man

Summary Serum zinc concentrations in peripheral venous blood were determined in 8 healthy volunteers at various times after oral administration of 50 mg Zn⁺⁺. The same dose was given to 6 patients surgically treated for obesity by jejuno-ileostomy. In the healthy volunteers the mean serum zinc concentration before dosing was 0.89 µg/ml and a mean peak concentration of 2.39 µg/ml was found after 3 h. In the patients the starting level was lower, 0.67 µg/ml, and a mean peak concentration of 1.31 µg/ml was found 90 min after treatment. In the patients the areas under the serum concentration-time curve was approximately 1/3 of that in the healthy subjects. Zn⁺⁺ 50 mg was also given to 3 patients undergoing transumbilical catheterization of the portal vein for diagnostic purposes and serum zinc concentrations were measured in portal and peripheral venous blood sampled simultaneously. No significant differences were found between the concentration of zinc in portal and peripheral venous blood during absorption, which suggests slow passage of zinc across the intestinal wall.     

Intestinal Absorption of Octreotide Using Trimethyl Chitosan Chloride: Studies in Pigs

Purpose. To investigate the enhancing effect of trimethyl chitosan chloride (TMC) on the enteral absorption of octreotide and to delineate the required doses of both TMC and peptide in vivo in juvenile pigs. Methods. Six female pigs (body weight, 25 kg) were operated to induce a stoma at the beginning of their jejunum and to insert an in-dwelling fistula for intrajejunal (IJ) administration of the formulations. A silicone cannula was inserted at the jugular vein for blood sampling. One week after surgery the pigs received IJ octreotide solution administrations with or without TMC at pH 7.4 or chitosan HCl at pH 5.5. For determining bioavailability (F) values, the pigs also received an octreotide solution intravenously (IV). Blood samples were taken from the cannulated jugular vein and subsequently analyzed by radioimmunoassay. Results. Intrajejunal administration of 10 mg octreotide without any polymer (control solution) resulted in F values of 1.7 ± 1.1% (mean ± SE). Chitosan HCl 1.5% (w/v) at pH 5.5 led to a 3-fold increase in F compared to the control (non-polymer containing) formulations. Co-administration of octreotide with 5 and 10% (w/v) TMC at pH 7.4 resulted in 7.7- and 14.5-fold increase of octreotide absorption, respectively (F of 13.9 ± 1.3% and 24.8 ± 1.8%). IJ administration of 5 mg octreotide solutions resulted in low F values of 0.5 ± 0.6%, whereas co-administration with 5% (w/v) TMC increased the intestinal octreotide bioavailability to 8.2 ± 1.5%. Conclusions. Cationic polymers of the chitosan type are able to enhance the intestinal absorption of the peptide drug octreotide in pigs. In this respect, TMC at neutral pH values of 7.4 appears to be more potent than chitosan HCl at a weak acidic pH of 5.5.     

Intestinal First-Pass Metabolism of Eperisone in the Rat

Purpose. The purpose of this study was to clarify quantitatively the contribution of the intestine to the first-pass metabolism of eperisone in rats. Methods. The systemic availabilities of eperisone were estimated by administering the drug into the duodenum, portal vein, and femoral vein in rats in vivo. The first-pass metabolism of eperisone was confirmed in the perfused rat small intestine in situ. Metabolism of eperisone to an -1-hydroxylated metabolite (HMO), the first step of eperisone metabolism, was studied using rat intestinal microsomes in vitro. Results. The bioavailabilities in the intestine were 0.176 and 0.0879 at administration rates of 100 and 25 mg/h/kg, respectively, whereas those in the liver were 0.532 and 0.486, respectively. In the intestinal perfusion experiment, the appearance clearance to the portal vein from the intestinal lumen was much lower than the elimination clearance from the intestinal lumen, resulting in high metabolic clearance of eperisone in the small intestine. Eperisone was biotransformed to HMO by rat intestinal microsomes, and this was inhibited by -naphthoflavone and an anti-rat CYP1A antibody. Conclusions. Those data strongly suggest that eperisone may be metabolized to HMO by CYP1A in rat intestinal microsomes during the first-pass through the epithelium of the small intestine.