Preclinical Pharmacokinetic Evaluation of β-Lapachone: Characteristics of Oral Bioavailability and First-Pass Metabolism in Rats

β-Lapachone has drawn increasing attention as an anti-inflammatory and anti-cancer drug. However, its oral bioavailability has not been yet assessed, which might be useful to develop efficient dosage forms possibly required for non-clinical and clinical studies and future market. The aim of the present study was thus to investigate pharmacokinetic properties of β-lapachone as well as its first-pass metabolism in the liver, and small and large intestines after oral administration to measure the absolute bioavailability in rats. A sensitive HPLC method was developed to evaluate levels of β-lapachone in plasma and organ homogenates. The drug degradation profiles were examined in plasma to assess the stability of the drug and in liver and intestinal homogenates to evaluate first-pass metabolism. Pharmacokinetic profiles were obtained after oral and intravenous administration of β-lapachone at doses of 40 mg/kg and 1.5 mg/kg, respectively. The measured oral bioavailability of β-lapachone was 15.5%. The considerable degradation of β-lapachone was seen in the organ homogenates but the drug was quite stable in plasma. In conclusion, we suggest that the fairly low oral bioavailability of β-lapachone may be resulted from the first-pass metabolic degradation of β-lapachone in the liver, small and large intestinal tracts and its low aqueous solubility.     

Pharmacokinetics of Oral 2′,3′-Dideoxyinosine in Rats

Pharmaceutical Research -     

Bioavailability and Pharmacokinetics of Isradipine after Oral and Intravenous Administration: Half‐Life Shorter than Expected?

Isradipine is a calcium channel‐blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half‐life of 8–9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half‐life was observed, and the present trial was therefore conducted in order to estimate the half‐life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross‐over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10–12 hr after administration and half‐life and bioavailability were estimated. Mean terminal half‐life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half‐life of isradipine seems to be of much shorter than demonstrated in previous oral studies.     

Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement of Monocarboxylate Transporters

Monocarboxylate transporter 1 (MCT1) has been previously reported as an important determinant of the renal reabsorption of the drug of abuse, gamma-hydroxybutyrate (GHB). Luteolin is a potent MCT1 inhibitor, inhibiting the uptake of GHB with an IC(50) of 0.41 microM in MCT1-transfected MDA-MB231 cells. The objectives of this study were to characterize the effects of luteolin on GHB pharmacokinetics and pharmacodynamics in rats, and to investigate the mechanism of the interaction using model-fitting methods. GHB (400 and 1,000 mg/kg) and luteolin (0, 4 and 10 mg/kg) were administered to rats via iv bolus doses. The plasma or urine concentrations of luteolin and GHB were determined by HPLC and LC/MS/MS, respectively. The pharmacodynamic parameter sleep time in rats after GHB administration was recorded. A pharmacokinetic model containing capacity-limited renal reabsorption and metabolic clearance was constructed to characterize the in vivo interaction. Luteolin significantly decreased the plasma concentration and AUC, and increased the total and renal clearances of GHB. Moreover, luteolin significantly shortened the duration of GHB (1,000 mg/kg)-induced sleep in rats (161 +/- 16, 131 +/- 14 and 121 +/- 5 min for control, luteolin 4 and 10 mg/kg groups, respectively, p < 0.01). An uncompetitive inhibition model, with an inhibition constant of 1.1 microM, best described the in vivo pharmacokinetic interaction. The results of this study indicated that luteolin significantly altered the pharmacokinetics of GHB by inhibiting its MCT1-mediated transport. The interaction between luteolin and GHB may offer a potential clinical detoxification strategy to treat GHB overdoses.     

γ-Hydroxybutyric Acid (GHB) Pharmacokinetics and Pharmacodynamics: Semi-Mechanistic and Physiologically Relevant PK/PD Model

An overdose of γ-hydroxybutyric acid (GHB), a drug of abuse, results in fatality caused by severe respiratory depression. In this study, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize monocarboxylate transporter 1 (MCT1)-mediated transport of GHB, as well as effects of GHB on respiration frequency, for IV doses of 200, 600, and 1500 mg/kg in rats. The proposed PK/PD model for GHB consists of nonlinear metabolism of GHB in the liver, MCT1-mediated renal reabsorption with physiologically relevant concurrent fluid reabsorption, MCT1-mediated uptake into the brain, and direct effects of binding of GHB to GABA_B receptors on the PD parameter, respiration frequency. Michaelis-Menten affinity constants for metabolism, renal reabsorption, and uptake into and efflux from the brain were fixed to the observed in vitro values. The IC ₅₀ value for the effect of GHB on respiration frequency was fixed to a reported value for binding of GHB to GABA_B receptors. All physiological parameters were fixed to the reported values for a 300-g rat. The model successfully captured the GHB PK/PD data and was further validated using the data for a 600-mg/kg dose of GHB after IV bolus administration. Unbound GHB brain ECF/blood partition coefficient (Kp _u,u ) values obtained from the model agreed well with values calculated using experimental ECF concentrations obtained with brain microdialysis, demonstrating the physiological relevance of this model. Sensitivity analysis indicated that the PK/PD model was stable. In conclusion, we developed a semi-mechanistic and physiologically relevant PK/PD model of GHB using in vitro drug-transporter kinetics and in vivo PK/PD data in rats.     

Absolute Oral Bioavailability and Metabolic Turnover of β-Sitosterol in Healthy Subjects

The metabolic turnover, absolute oral bioavailability, clearance, and volume of distribution for β-sitosterol were measured in healthy subjects. [(14)C]β-Sitosterol was used as an isotopic tracer to distinguish pulse doses from dietary sources and was administered by both oral and intravenous routes. The administered doses of [(14)C]β-sitosterol were in the region of 3 to 4 μg, sufficiently low as not to perturb the kinetics of β-sitosterol derived from the diet. Because the plasma concentrations of [(14)C]β-sitosterol arising from such low doses were anticipated to be very low, the ultrasensitive isotope ratio analytical method of accelerator mass spectrometry was used. The limit of quantification for [(14)C]β-sitosterol was approximately 0.1 pg/ml, the oral absolute bioavailability was just 0.41%, clearance was 85 ml/h, volume of distribution was 46 L, and the turnover was 5.8 mg/day. Given the steady-state concentrations of β-sitosterol (2.83 μg/ml), then the dietary load was calculated to be approximately 1400 mg/day.     

Intestinal Transport of Sulfanilic Acid in Rats Immunized with Protein–Sulfanilic Acid Conjugate

Intestinal transport of sulfanilic acid was examined by means of an in vitro everted sac technique in rats immunized with a bovine -globulin–sulfanilic acid conjugate. At a low concentration of sulfanilic acid, the intestinal transport of sulfanilic acid was decreased in rats immunized with bovine -globulin–sulfanilic acid conjugate. This phenomenon was dose dependent and antigen specific, since there was no difference in the transport of sulfanilic acid at a high concentration and of an unrelated hapten. These results suggested that parenteral immunization impaired not only the intestinal transport of macromolecular antigens, as previously shown, but also the transport of the low molecular weight hapten, sulfanilic acid.     

Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its β-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-γ-CyD < G₂-β-CyD < β-CyD < HP-β-CyD. Spectroscopic studies also revealed that HP-β-CyD and β-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-β-CyD ≤ β-CyD. HP-β-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-β-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its β-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-β-CyD complex were much higher than in either that of rutin alone or in its β-CyD complex. The in vivo absorption study suggests that HP-β-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-β-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.     

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

The transport of monocarboxylates, such as lactate and pyruvate, is mediated by the SLC16A family of proton-linked membrane transport proteins known as monocarboxylate transporters (MCTs). Fourteen MCT-related genes have been identified in mammals and of these seven MCTs have been functionally characterized. Despite their sequence homology, only MCT1-4 have been demonstrated to be proton-dependent transporters of monocarboxylic acids. MCT6, MCT8 and MCT10 have been demonstrated to transport diuretics, thyroid hormones and aromatic amino acids, respectively. MCT1-4 vary in their regulation, tissue distribution and substrate/inhibitor specificity with MCT1 being the most extensively characterized isoform. Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including gamma-hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide. MCTs are expressed in a wide range of tissues including the liver, intestine, kidney and brain, and as such they have the potential to impact a number of processes contributing to the disposition of xenobiotic substrates. GHB has been extensively studied as a pharmaceutical substrate of MCTs; the renal clearance of GHB is dose-dependent with saturation of MCT-mediated reabsorption at high doses. Concomitant administration of GHB and L: -lactate to rats results in an approximately two-fold increase in GHB renal clearance suggesting that inhibition of MCT1-mediated reabsorption of GHB may be an effective strategy for increasing renal and total GHB elimination in overdose situations. Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCT-mediated detoxification strategies in GHB overdose.     

Comparison of the Pharmacokinetics of Oxycodone and Noroxycodone in Male Dark Agouti and Sprague–Dawley Rats: Influence of Streptozotocin-Induced Diabetes

Purpose The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague–Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains.Methods High-performance liquid chromatography–electrospray ionization–tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats.Results The mean (±SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p < 0.05; nondiabetic, p < 0.005). Serum concentrations of oxymorphone were very low (<6.9 nM).Conclusions Both DA and SD rats are suitable rodent models to study oxycodone’s pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent μ-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.     

Use of a Local Sensitivity Analysis to Inform Study Design Based on a Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid

γ-Hydroxybutyric acid (GHB), a drug of abuse, demonstrates complex toxicokinetics with capacity-limited metabolism and active renal reabsorption. The objectives of the present study were to conduct a local sensitivity analysis of a mechanistic model for the active renal reabsorption of GHB and to use the results to inform the design of future studies aimed at developing therapeutic strategies for treating GHB overdoses. A local sensitivity analysis was used to assess the influence of parameter perturbations on model outputs (plasma concentrations and urinary excretion of GHB). Further, a sensitivity index was calculated for each perturbed parameter to assess the specific segments of the time course that are critical to parameter estimation. Model outputs were simulated for rats dosed with 200, 400, 600, and 1,000 mg/kg GHB intravenously and individual parameters were perturbed by two-, five-, and tenfold higher and lower than the nominal value. Model outputs were sensitive to perturbations in clearance and volume parameters. In contrast, model outputs were found to be insensitive to changes in distributional parameters suggesting that additional tissue distribution data is required. Based on the sensitivity analysis the 1,000-mg/kg GHB dose can be eliminated from future studies as the parameters can be adequately estimated from the lower doses. To further validate the use of this model, dose-specific sampling schedules were designed based on model predictions for doses of 600 and 1,500 mg/kg. These sampling schedules were able to adequately capture the inflection point and terminal elimination phase of the plasma concentration-time profiles obtained.     

Pharmacokinetics of theophylline in patients with COPD and its interference factors

AIM： To study the pharmacokinetics of theophylline in patients with chronic obstructive pulmonary diseases （COPD） and its interference factors. METHODS： Serum theophylline concentrations in 9 patients with COPD after oral administration of theophylline （200 mg, tid） for 5 consecutive days or combining with nifedipine （ 10 mg, tid） for 5 consecutive days were determined by high performance liquid chromatography（HPLC） with ultraviolet spectrophotometry. RESULTS： The pharmacokinetics of theophylline in COPD patients was one-compartment model after oral administration of theophylline （200 mg, tid） for 5 consecutive days. The significant difference in individual variation on pharmacokinetics of theophylline was observed in this study. The volume of distribution （ Vd ） was （0.50 ± 0.21） L/kg, the elimination half-life （ t1/2 ） was （5.4 ± 1.3） h and clearance （CL） was （0.07 ± 0.03） L·h^-1·kg^-1 in the patients with COPD. There was no significant difference in Vd, t1/2, and CL between COPD patients and healthy volunteers （ P 〉 0.05）. The values of k and C1 were faster and t 1/2 was shorter in the middleaged patients than those in old COPD patients （P 〈 0.05）.[第一段]     

Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy

γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacity-limited metabolism. The objectives of this study were to construct a mechanistic toxicokinetic (TK) model describing saturable renal reabsorption and capacity-limited metabolism of GHB and to predict the effects of inhibition of renal reabsorption on GHB TK in the plasma and urine. GHB was administered by iv bolus (200–1,000 mg/kg) to male Sprague-Dawley rats and plasma and urine samples were collected for up to 6 h post-dose. GHB concentrations were determined by LC/MS/MS. GHB plasma concentration and urinary excretion were well-described by a TK model incorporating plasma and kidney compartments, along with two tissue and two ultrafiltrate compartments. The estimate of the Michaelis-Menten constant for renal reabsorption (K _m,R) was 0.46 mg/ml which is consistent with in vitro estimates of monocarboxylate transporter (MCT)-mediated uptake of GHB (0.48 mg/ml). Simulation studies assessing inhibition of renal reabsorption of GHB demonstrated increased time-averaged renal clearance and GHB plasma AUC, independent of the inhibition mechanism assessed. Co-administration of GHB (600 mg/kg iv) and l-lactate (330 mg/kg iv bolus plus 121 mg/kg/h iv infusion), a known inhibitor of MCTs, resulted in a significant decrease in GHB plasma AUC and an increase in time-averaged renal clearance, consistent with the model simulations. These results suggest that inhibition of renal reabsorption of GHB is a viable therapeutic strategy for the treatment of GHB overdoses. Furthermore, the mechanistic TK model provides a useful in silico tool for the evaluation of potential therapeutic strategies.     

Physiologically Based Pharmacokinetics of Cyclosporine A: Reevaluation of Dose–Nonlinear Kinetics in Rats

The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide iv dose range (1.2–30mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CL_b ). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vu_ss ) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis–Menten kinetics, K_m 0.60 g/ml. In model-based simulations, both volume of distribution at steady state (V _ss,b ) and CL_b varied in a similar manner with dose, such that terminal t _1/2 remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood–brain barrier.     

The Pharmacokinetics of Pancuronium in Infants,Children and Adults

研究观察年龄对潘库溴铵药代动力学的影响。选择２４例施择期整形外科手术的患者，根据年龄分成三组：１组为５例婴幼儿，年龄０．７５～２．９５岁；２组为１３例儿童，年龄４～１４岁；３组为６例成人，年龄１６～２７岁。静注潘库溴铵１００μｇ／ｋｇ后用改良荧光法测定其血浓度。潘库溴铵的体内过程能用二室开放模型完整描述，年龄愈小，分布容积愈大，血浆清除率愈高，潘库溴铵的血药浓度愈低。Ｖ１（中央室分布容积）、Ｖ２（周边室分布容积）、Ｖｄｓｓ（稳态分布容积）、Ｃｌ（血浆清除率）和ＡＵＣ（曲线下面积）在三组间有明显差别。１组的Ｔ１／２β和ＭＲＴ明显比２、３组长，但Ｔ１／２α和Ｋ２１在三组间无明显差别。     

Stereoselectivity in Pharmacokinetics of Rivoglitazone,A Novel Peroxisome Proliferator-Activated Receptor γ Agonist,in Rats and Monkeys: Model-Based Pharmacokinetic Analysis and In Vitro-In Vivo Extrapolation Approach

Stereoselectivity in pharmacokinetics of rivoglitazone, a novel peroxisome proliferator-activated receptor γ agonist, in rats and monkeys was examined. The pharmacokinetic model involving chiral inversion explained well the plasma profiles of R-isomer and S-isomer after intravenous and oral administration of (R)-rivoglitazone or (S)-rivoglitazone to rats and monkeys. The high stereoselectivity was evaluated in chiral inversion clearance (R/S ratio: 7.92), metabolic clearance (5.78), and volume of distribution (4.04) in rats; however, these were low (1.73, 1.31, and 1.06) in monkeys. The stereoselectivity in chiral inversion was also observed in in vitro incubation studies in plasma, and the R/S ratio of chiral inversion showed high correlation with the R/S ratio of plasma unbound fraction. The metabolic clearance of the primary five metabolic pathways of rivoglitazone was evaluated from an in vitro–in vivo extrapolation approach using rat and monkey liver microsomes. The high stereoselectivity in metabolic clearance in rat was evaluated (R/S ratio: 5.78), which was assumed to be because of the stereoselectivity in plasma unbound fraction, on the contrary, that in monkeys exhibited low stereoselectivity (0.774). Thus, the stereoselectivity in plasma unbound fraction was estimated to be a major determinant of stereoselectivity in pharmacokinetics of rivoglitazone in rats and monkeys.     

Biodegradable Nanoparticles Improve Oral Bioavailability of Amphotericin B and Show Reduced Nephrotoxicity Compared to Intravenous Fungizone®

Purpose

Amphotericin B (AMB), an effective antifungal and antileishmanial agent associated with low oral bioavailability (0.3%) and severe nephrotoxicity, was entrapped into poly(lactide-co-glycolide) (PLGA) nanoparticles to improve the oral bioavailability and to minimize the adverse effects associated with it.

Materials and Methods

The AMB-nanoparticles (AMB-NP) were prepared by nanoprecipitation method employing Vitamin E-TPGS as a stabilizer. In vitro release was carried out using membrane dialysis method. The in vitro hemolytic activity of AMB-NP was evaluated by incubation with red blood cells (RBCs). The acute nephrotoxicity profile and oral bioavailability of AMB-NP were evaluated in rats.

Results

The prepared AMB-NP formulation contained monodispersed particles in the size range of 165.6?±?2.9 nm with 34.5?±?2.1% entrapment at 10% w/w initial drug loading. AMB-NP formulation showed biphasic drug release, an initial rapid release followed by a sustained release. The AMB-NP formulation exerted lower hemolysis and nephrotoxicity as compared to Fungizone®. The relative oral bioavailability of the AMB-NP was found to be ～800% as compared to Fungizone®.

Conclusion

Together, these results offer a possibility of treating systemic fungal infection and leishmaniasis with oral AMB-NP, which could revolutionize the infectious disease treatment modalities.

     

Pharmacokinetics of a Single Intravenous and Oral Dose of Pafenolol—a Beta1Adrenoceptor Antagonist with Atypical Absorption and Disposition Properties—in Man

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 µCi [³H]pafenolol. The plasma concentration–time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 ± 0.2 and 3.7 ± 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 ± 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t _1/2l was 6.6 ± 1.8 min. The volumes of distribution were V _c = 0.22 ± 0.08 liter/kg, V _ss = 0.94 ± 0.17 liter/kg, and V _z = 1.1 ± 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 ± 5.1% of the given dose and in the feces to 23.8 ± 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 ± 5.9 and 67.0 ± 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 ± 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 ± 31, 31 ± 15, and 95 ± 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 ± 0.3 hr for the iv dose and 6.7 ± 0.7 hr for the oral dose.