Comparison of plasma cocaine levels during a "binge" pattern of cocaine administration in male and female rhesus monkeys

Abstract Rationale. Cocaine is often abused in a "binge" pattern, but little is known about changes in plasma cocaine concentrations or cocaine pharmacokinetics during administration of multiple cocaine doses. Moreover, the extent to which gender may influence plasma cocaine levels during a cocaine binge has not been studied in rhesus monkeys. Objectives. To compare the effects of repeated injections of the same dose of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) on plasma cocaine concentrations, cocaine pharmacokinetics and behavioral responses in male and female rhesus monkeys. Methods. Four injections of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) were administered at 30-min intervals to five or six male and five or six female rhesus monkeys. Samples for plasma cocaine analysis were collected at 2, 4, 8, 16 and 24 min after the first three injections. After the fourth cocaine injection, additional samples were collected at 10-min intervals over 150 min. Results. Plasma cocaine peaks and nadirs increased monotonically after successive cocaine injections (P<0.0001). Peak plasma cocaine levels measured at 2 min after cocaine administration were higher after 0.8 mg/kg cocaine than after 0.4 mg/kg cocaine (P<0.006). There were no significant gender differences in time to peak plasma cocaine levels (t_max), peak cocaine concentrations (C_max) or half-life (t_1/2; min) at either dose of cocaine. Group average behavioral ratings were similar in males and females after each dose of cocaine. Conclusions. Peak plasma cocaine concentrations increased progressively during low and high dose cocaine binge episodes, and there were no significant gender differences in cocaine pharmacokinetics. These findings demonstrate the feasibility of simulating "binge" patterns of cocaine administration in rhesus monkeys. Electronic Publication     

Comparative kinetics of digoxin in serum and vitreous humor in a guinea pig model. II. Single oral dose administration.

In a continuation of work previously reported involving the comparative kinetics of digoxin in vitreous humor and serum after an intravenous dose, the present report describes the pharmacokinetics of digoxin in this model following the administration of a single oral dose. Serum and vitreous humor concentrations of digoxin were monitored by radioimmunoassay for 720 min after a single oral dose of 0.1 mg digoxin/kg. Serum concentrations peaked by 60 min and declined over the remaining observation period with a half-life of 360 min. Vitreous humor concentrations lagged behind the serum concentrations, peaked between 60 and 120 min, and then declined at a rate less than that of serum with convergence of concentration occurring in the 720-min samples. The vitreous humor-serum ratios ranged from a low of 0.003 (15 min) to a high of 0.98 at convergence. The impact of these findings upon forensic toxicologic practice is reviewed.     

Microdialysis Evaluation of the Ocular Pharmacokinetics of Propranolol in the Conscious Rabbit

Purpose. This study was conducted to assess the effects of anesthesia and aqueous humor protein concentrations on ocular disposition of propranolol. Methods. Rabbits were anesthetized and a microdialysis probe was inserted into the anterior chamber of one eye; the contralateral eye served as a control. At timed intervals after probe placement, a 100-l sample of aqueous humor was aspirated from each eye to determine protein concentration. In vitro protein binding parameters were used to simulate the impact of protein concentration on propranolol disposition. To assess the influence of anesthesia, probes were implanted in the anterior chamber of each eye. After >5-day stabilization, conscious and anesthetized rabbits (n = 3/group) received a 200-g topical dose of [³H] DL-propranolol in each eye; propranolol was assayed in probe effluent. Results. Changes in aqueous humor protein concentrations were observed following probe insertion. Simulations demonstrated that the unbound propranolol AUC (2.4-fold) in aqueous humor should be reduced due to protein influx. Intraocular propranolol exposure in anesthetized rabbits was 8-fold higher than in conscious rabbits, and 1.9-fold higher than in rabbits without a post-surgical recovery period. Conclusions. Anesthesia and time-dependent aqueous humor protein concentrations may alter ocular pharmacokinetics, and must be taken into account in the design of microdialysis experiments.     

Toxicology and Toxicokinetics of Acute and Subchronic Administration of Histamine Dihydrochloride in Rats

Abstract

Histamine dihydrochloride is currently being evaluated as an adjuvant to immunotherapy regimens in neoplastic and infectious diseases. The no-observed-effect-level (NOEL), no-observable-adverse-effect-level (NOAEL), and pharmacokinetics of subcutaneously administered histamine dihydrochloride were determined via 5 and 28 day repeated dose studies in Sprague-Dawley rats. In the five day study, male rats received 0 (vehicle), 5, 30, 500, or 1000 mg/kg BID. Acute tissue damage was observed at one or more injection sites in the two highest dose groups after 24 h. At five days, animals in these groups displayed indications of pathological inflammation at the injection sites. In the 28 day study, male and female rats received 0 (vehicle), 0.5, 5, or 100 mg/kg BID. The most significant treatment-related pathological findings were signs of inflammation at the injection sites for animals in the 100 mg/kg BID group. Hematology and clinical chemistry changes in the highest dose groups in both studies were consistent with inflammation and anemia but were found to be reversible following a 14-day recovery. Plasma histamine levels were quantified from male and female animals receiving 0.5, 5, and 100 mg/kg injections on Day 1 and 28 of the twenty-eight day study. C_max was achieved within 0.25 h and was dose-proportional. The elimination half-life and t_max were longer at the 100 mg/kg dose than the lower doses. No marked differences between genders or between Day 1 and 28 were found. Based on these findings, the NOEL and NOAEL were established at 0.5 mg/kg BID and 5 mg/kg BID, respectively. When converted to human equivalent dose, the NOAEL is 0.81 mg/kg which is 54 times the intended human dose. These studies support a wide safety margin for histamine dihydrochloride.     

Comparative kinetics of serum and vitreous humor digoxin concentrations in a guinea pig model. Part I: Intravenous administration of digoxin

The pharmacokinetics of a single intravenous dose of digoxin in the guinea pig was investigated with emphasis on the penetration of digoxin into the vitreous humor. A controlled study was undertaken and data was collected which indicated that digoxin follows an open, two-compartment pharmacokinetic model with a terminal half-life of 318 minutes. The data indicated that the ratio of vitreous concentrations to serum concentrations were determined to be equal following an initial tissue distribution phase.     

Venous Irritation,Pharmacokinetics, and Tissue Distribution of Tirilazad in Rats Following Intravenous Administration of a Novel Supersaturated Submicron Lipid Emulsion

Purpose. To compare the venous irritation, pharmacokinetics, and tissue distribution of tirilazad in rats after intravenous administration of a submicron lipid emulsion with that of an aqueous solution. Methods. Venous irritation was determined by microscopic evaluation of injury to the lateral tail veins of rats. Pharmacokinetic parameters were determined by following plasma concentrations of drug. Tissue distribution of [¹⁴C]-tirilazad was determined by quantitative whole body autoradiography. Results. Single dose injections of tirilazad as an emulsion at doses ranging from 1.52 mg to 13.5 mg were non-irritating whereas the solution was irritating at a dose of 1.3 mg. The pharmacokinetic parameters were not statistically different between the emulsion and the solution (p > 0.2) at doses of 6 mg/kg/day and 20 mg/kg/day. However, at 65 mg/kg/day dose, a higher AUC(0,6) (4-fold) and lower V_ss (18-fold) and CL(5-fold) were observed for the lipid emulsion as compared to the solution (p < 0.05). Tissue distribution showed higher initial concentrations (two fold or more) in most tissues for the solution. These values, however, equilibrated by 4 h and AUC(0,4) differences were less than two fold in most tissues. Conclusions. Formulating tirilazad in the lipid emulsion significantly reduces the venous irritation without changing the pharmacokinetics and tissue distribution at low doses.     

Dose-Dependent Pharmacokinetics of Warfarin in Healthy Volunteers

Purpose. To examine the pharmacokinetics of warfarin after administration of single oral doses (2, 5, and 10 mg) to healthy male volunteers. Methods. A sensitive reverse-phase HPLC method was used to quantify warfarin plasma concentrations as low as 6 ng/ml. Blood samples were collected for up to 120 hours following administration of these doses. Results. As the dose decreased from 5 to 2 mg, the apparent volume of distribution (V/F) increased from 12 to 21 liters and the terminal half-life (t_1/2) increased from 47 to 71 hours. Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t_1/2 and V/F may be due to saturable tissue binding of this drug. It appears that a previously undetected and prolonged terminal phase may exist but can not be adequately characterized with the 120-hour sampling interval. To evaluate this long t_1/2, a follow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase started to become apparent when plasma levels declined to less than 100 ng/ml. The t_1/2 of this terminal phase was determined to be approximately one week. Conclusions. This is the first report that documents the dose-dependent pharmacokinetics of warfarin and the previously unreported long t_1/2 of one week for warfarin in humans.     

Pharmacokinetics of Monoclonal Antibody and Antibody Fragments in The Mouse Eye Following Intravitreal Administration

Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection, and analysis of drug concentrations. Therefore, ocular PK of protein therapeutics in mouse eye following intravitreal (IVT) administration is not known. Here, we have presented the first of its kind investigation, to study the PK of 4 different size non-binding protein therapeutics in mouse plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) following IVT administration. Administered proteins include trastuzumab (150 kDa) and F(ab)₂ (100 kDa), Fab, and scFv (27 kDa) fragments of trastuzumab. An imaging and injection apparatus suitable for performing small (50 nL) IVT injections in mice was developed, and techniques for enucleation of the eye and dissection of ocular tissues were developed. Furthermore, a sensitive enzyme-linked immunosorbent assay (ELISA) for detection of proteins in very small amounts of ocular tissues were developed. It was observed that elimination from the vitreous chamber was the primary driver of PK in the cornea/ICB, retina, posterior cup, and plasma. Trastuzumab displays first-order kinetics in the vitreous humor with a half-life of 18.8 h. F(ab)₂, Fab, and ScFv show biphasic PK profiles with distribution phases becoming more rapid as molecular weight decreases, and terminal elimination becoming longer as molecular weight decreases, with terminal half-lives of 16.3, 20.6, and 48.9 h, respectively. The mean residence times of trastuzumab, F(ab)₂, Fab, and scFv in the vitreous humor were 26.0, 12.2, 10.7, and 8.16 h, respectively. It was found that the mean residence time in vitreous humor doubles with an increase in molecular weight of ∼69 kDa. Interestingly, the PK of proteins measured in the un-injected eye suggest the presence of a pathway for drug transfer between the eyes, which needs to be further validated. Overall, the findings presented here pave the way for drug discovery and development studies of protein therapeutics for ophthalmic indications in mice.     

Ocular Pharmacokinetic Study Using T<Subscript>1</Subscript> Mapping and Gd-Chelate- Labeled Polymers

Purpose  

Recent advances in drug discovery have led to the development of a number of therapeutic macromolecules for treatment of posterior eye diseases. We aimed to investigate the clearance of macromolecular contrast probes (polymers conjugated with Gd-chelate) in the vitreous after intravitreal injections with the recently developed ms-DSEPI-T12 MRI and to examine the degradation of disulfide-containing biodegradable polymers in the vitreous humor in vivo.     

An analysis of some discriminative properties of d-amphetamine

Male albino rats were trained and tested on a two-lever discrimination task based upon the presence or absence of d-amphetamine (1.0 mg/kg). This compound was found to produce strong discriminative cues (i.e., 90% correct choice behavior). A dose-effect function was then ascertained and the discriminative ED₅₀ (following training with 1.0 mg/kg) was found to be 0.23 mg/kg d-amphetamine.In order to determine the effective duration of d-amphetamine action, the interval between injection and testing was varied; it was found that the discriminative effects of the drug began to dissipate between 60 and 90 min post-injection.In an attempt to compare the discriminative cues of other drugs with those of d-amphetamine, injections of LSD (0.04 and 0.08 mg/kg), psilocybin (0.50 and 1.0 mg/kg), THC (0.50 and 1.0 mg/kg), mescaline (5.0 and 10.0 mg/kg), and caffeine (6.0 and 20.0 mg/kg) were given during extinction. In all cases, the rats responded predominantly on the saline-related lever. Only methamphetamine (1.0 mg/kg) produced d-amphetamine-like responding.Finally, alpha-methyl-para-tyrosine (AMPT), a compound which depletes brain catecholamines (CA), was found to disrupt the d-amphetamine-saline discrimination.     

金黄色葡萄糖球菌肠毒素C2改构蛋白大鼠药动学研究

目的 研究金黄色葡萄糖球菌肠毒素C2改构蛋白（2M-118）在大鼠体内单次和多次给药后的药动学特征。方法 24只大鼠随机分为3组,每组8只,雌雄各半,分别单次iv低、中和高剂量（1、2和4 mg/kg）2M-118,高剂量组大鼠于单次给药后,继续每天给药1次,共给药8次。于给药前（0 h）,首次及末次给药后5、10、20、30、45 min和1.0、1.5、2.0、4.0、6.0、8.0 h采集眼静脉丛全血约0.5 mL,制备血清。采用双抗体夹心酶联免疫吸附测定（ELISA）法检测大鼠血清药物浓度,采用DAS 3.2.8药动程序计算药动学参数。结果 大鼠单次iv 2M-118后,在1～4 mg/kg剂量内,峰浓度（C_max）、初始浓度（C₀）和药时曲线下面积（AUC）均与剂量呈正相关;消除相半衰期（t_1/2Z）随剂量递增明显延后,平均t_1/2z分别为0.24、0.60和1.18 h;表观分布容积（V_z）随剂量递增而增大;各剂量组的清除率（CL_z）较为一致。与同剂量（4 mg/kg）单次给药相比,大鼠多次给药后的主要药动学参数基本保持一致,体内药物无蓄积倾向。结论 大鼠单次iv 2M-118后,在1～4 mg/kg剂量内,体内暴露量与剂量呈正相关,其清除可能呈现非线性动力学特征;单次与多次iv给予相同剂量2M-118后,药动学行为特征基本一致,无明显药物蓄积。     

Calculation of AQCmax: comparison of five ophthalmic fluoroquinolone solutions

ABSTRACT

Objective: Ocular tissue penetration of five different ophthalmic fluoroquinolone solutions in the rabbit eye was measured and evaluated by an index of the maximum aqueous concentration (AQCmax).

Methods: Moxifloxacin 0.5% (MFLX), levofloxacin 0.5% (LVFX), gatifloxacin 0.3% (GFLX), ofloxacin 0.3% (OFLX), or tosufloxacin tosilate 0.3% (TFLX) were instilled into the eyes of white rabbits every 15?min for a total of three doses. Aqueous humor, cornea, iris/ciliary body and vitreous body were collected 10 to 240?min after instillation and drug concentrations were measured by high-performance liquid chromatography.

Results: The concentration of MFLX was the highest in each tissue, with maximum concentrations of MFLX in the aqueous humor (10.16?±?1.59?µg/mL) at 30?min after instillation, cornea (156.07?±?95.97?µg/g) and iris/ciliary body (11.92?±?4.00?µg/g) at 10?min after instillation, and vitreous body (0.099?±?0.033?µg/mL) at 30?min after instillation. The concentration of TFLX was the lowest in each tissue, with LVFX, GFLX, and OFLX sharing the mid-ranks. AQCmax?:?MIC₉₀ ratio for S.?aureus was 150.67 for MFLX, 10.6 for LVFX, 9.69 for GFLX, 3.48 for OFLX, and could not be determined for TFLX.

Conclusion: AQCmax is a useful pharmacokinetic parameter for determining the therapeutic efficacy of an ophthalmic antibiotic, especially when combined with MIC₉₀ values for intraocular pathogens. C_max of MFLX ophthalmic solution was superior in all tissues (cornea, aqueous humor, iris/ciliary body and vitreous body) among the five ophthalmic solutions studied, exceeding the MIC₉₀ of S.?aureus in all tissues, and MIC₉₀s of S.?epidermidis, B.?cereus, and P.?acnes in aqueous humor, cornea, and iris/ciliary body. AQCmax was approximately proportional to C_max in iris/ciliary body and vitreous, and may be used in combination with MIC₉₀s as an index to predict the most appropriate dose and frequency of ophthalmic antibiotics in conjunction with other PK/PD parameters. This study may provide the groundwork for calculation of AQCmax in humans.     

Computer Simulation of Convective and Diffusive Transport of Controlled-Release Drugs in the Vitreous Humor

Purpose. Biodistribution of drugs in the eye is central to the efficacy of pharmaceutical ocular therapies. Of particular interest to us is the effect of intravitreal transport on distribution of controlled-released drugs within the vitreous. Methods. A computer model was developed to describe the three-dimensional convective-diffusive transport of drug released from an intravitreal controlled release source. Unlike previous studies, this work includes flow of aqueous from the anterior to the posterior of the vitreous. The release profile was based on in vitro release of gentamicin from poly(L-lactic acid) microspheres into vitreous. Results. For small drugs, convection plays a small role, but for large (slower diffusing) drugs, convection becomes more important. For the cases studied, the predicted ratio of drug reaching the retina to drug cleared by the aqueous humor was 2.4 for a small molecule but 13 for a large molecule. Transport in neonatal mouse eye, in contrast, was dominated by diffusion, and the ratio decreased to 0.39. Conclusions. The interaction among convection, diffusion, and geometry causes significant differences in biodistribution between large and small molecules or across species. These differences should be considered in the design of delivery strategies or animal studies.     

The Effect of Food on the Absorption of Controlled-Release Theophylline in Mini-Swine

The effect of differing fat contents of food on the bioavailability of theophylline following a 400-mg single dose of Theo-24 was studied in mini-swine. The pharmacokinetics of theophylline, following the intravenous administration of aminophylline equivalent to 5 mg/kg as a single dose, were also studied in the same animals. The terminal plasma half-life of theophylline following an i.v. dose was found to be approximately 24 hr. The volume of distribution, V _dext, and clearance following the i.v. dose were approximately 0.7 liter/kg and 0.023 liter/hr/kg, respectively. The terminal half-life of theophylline following the administration of theophylline capsules under fasting conditions was 21 hr. The average bioavailability under fasting conditions was approximately 80% compared to the i.v. dose. Food appeared to have decreased the rate of absorption but no significant effect on the extent of absorption.     

Pre-clinical pharmacokinetics and acute toxicological evaluation of a monastrol derivative anticancer candidate LaSOM 65 in rats

Abstract

1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats.

2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1?mg/kg) and oral (p.o., 10 and 30?mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5?mg/kg) and p.o. (50, 100 and 150?mg/kg) administration.

3. Short half-life (1.75?±?0.71?h), a clearance of 0.85?±?0.18?L/h/kg and a volume of distribution of 1.76?±?0.24?L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3?h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects.

4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate.     

Potential of liposomes for the intravitreal injection of therapeutic molecules

Intravitreal administration has been widely used since 20 years and has been shown to improve the treatment of diseases of the posterior segment of the eye with infectious origin or in edematous maculopathies. This route of administration allows to achieve high concentration of drug in the vitreous and avoids the problems resulting from systemic administration. However, two basic problems limit the use of intravitreal therapy. Many drugs are rapidly cleared from the vitreous humor; therefore, to reach and to maintain effective therapy repeated injections are necessary. Repeated intravitreal injections increase the risk of endophthalmitis, damage to lens, retinal detachment. Moreover, some drugs provoke a local toxicity at their effective dose inducing side-effects and possible retinal lesions. In this context, the development and the use of new drug delivery systems for intravitreal administration are necessary to treat chronic ocular diseases. Among them, particulate systems such as liposomes have been widely studied. Liposomes are easily injectable and permit to reduce the toxicity and to increase the residence time of several drugs in the eye. They are also able to protect in vivo poorly-stable molecules from degradation such as peptides and nucleic acids. Some promising results have been obtained for the treatment of retinitis induced by cytomegalovirus in human and more recently for the treatment of uveitis in animal. Finally, the fate of liposomes in ocular tissues and fluids after their injection into the vitreous and their elimination routes begin to be more known.     

Tolerance to the discriminative stimulus properties of d-amphetamine

Male rats (F-344) responding for milk on a VI 20 sec schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with d-amphetamine (0.50, 1.00 or 1.50 mg/kg) or saline 15 min prior to daily training sessions. Dose-response functions determined for each of the three (n = 6) training-dose groups indicated that ED₅₀ values were directly correlated with training dose. Two days following chronic amphetamine injections (a total of 78 mg/kg over 4 days) rats were tested for tolerance at a dose which normally produced about 80% drug-lever responding. Rats in all three groups showed tolerance to the cue properties of amphetamine. In the 0.50 and 1.00 mg/kg groups, complete tolerance was shown as evidenced by the fact that the drug lever responding did not differ from that which was appropriate following saline injections.     

Chloroquine concentrations in the eye of dogs given chloroquine, primaquine, or p,p'-sulfonyl-bisformanilide, alone or in combination

An assay procedure for chloroquine (CQ) was adapted to vitreous humor and eye tissues. Eye tissues without cornea were minced, digested overnight in 10% KOH, and homogenized before assaying. The presence of primaquine (PQ) slightly increased the recovery of CQ. Both the vitreous humor and the eye tissues of dogs receiving CQ, contained the compound. The concentration of CQ accumulated in the eye after prolonged administration and was proportional to the dose. The eye tissues contained 50–448 times more CQ than did the vitreous humor. In one study, simultaneous administration of DFD increased CQ concentrations in both the vitreous humor and the eye tissues. However, this effect was not observed in two other studies. The vitreous humor and the eye tissues of dogs receiving PQ alone, or PQ plus DFD, contained small but measurable readings in the CQ assay. We believe that these small readings of CQ were actually due to the presence of PQ, suggesting that PQ was also absorbed after oral administration and was present in the eye.     

Intravitreal kinetics of hesperidin, hesperetin, and hesperidin G: effect of dose and physicochemical properties

Hesperidin, a flavanone glycoside, and its aglycone hesperetin are potential candidates for the treatment of diabetic retinopathy and macular edema. The objective of this study was to delineate vitreal pharmacokinetics of hesperidin and hesperetin and the hydrophilic derivative glucosyl hesperidin (hesperidin G) following intravitreal administration in anaesthetized rabbits. Concentration changes in vitreous humor were monitored using microdialysis sampling procedure. All three molecules were administered intravitreally at three dose levels (50 μL injection volume containing 1.5, 4.5, and 15 μg of the drug, resulting in a final vitreal concentration of 1, 3, and 10 μg/mL). Vitreal microdialysis samples were collected every 20 min over a period of 10 h. All three molecules exhibited linear pharmacokinetics within the dose range tested because area under the curve and maximum concentration (C(max) ) increased linearly with increasing dose and a significant difference in the elimination parameters such as clearance or half-life was not observed. The vitreal elimination half-life of these three compounds was observed to correlate with the molecular weight and lipophilicity of the molecules. The findings from this study provide practical information that will be useful in the future design of ocular drug delivery strategies for bioflavonoids.     

Absorption and Disposition of a Selective Aldosterone Receptor Antagonist,Eplerenone, in the Dog

Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.