Absorption, first-pass metabolism, and disposition of itraconazole in rats

This study examined the pharmacokinetic disposition, oral absorption and hepatic extraction of itraconazole and its active metabolite, hydroxyitraconazole, in rats. After i.v. injection, serum itraconazole concentrations decreased biexponentially, with an average terminal elimination half-life, volume of distribution and systemic clearance of 4.9 h, 6.0 l/kg and 14.2 ml/min/kg, respectively. When given orally, its absorption was low, with a mean absolute bioavailability of 16.6%. The metabolite to parent drug area under the curve (AUC) ratio was higher after oral administration compared with i.v. injection (mean ratio, 2.7 vs. 0.9). The hepatic drug extraction ratio determined after femoral and portal vein administration averaged 18.5%. When hydroxyitraconazole was injected i.v., the elimination half-life, volume of distribution and systemic clearance of itraconazole averaged 10.0 h, 2.4 l/kg and 3.4 ml/min/kg, respectively. The fraction of the systemically available itraconazole that was metabolized to hydroxyitraconazole was 21.0% and 76.0% after i.v. and oral administration, respectively. In summary, this study is the first reporting the hepatic extraction of itraconazole and the i.v. disposition characteristics of hydroxyitraconazole in rats. Itraconazole is a drug with a low hepatic extraction ratio and its systemic clearance appears to be largely accounted for by hepatic metabolism.     

Pharmacological properties of galenical preparation. XV. Pharmacokinetics study of evocarpine and its metabolite in rats.

It is known that when methanol extract of Evodia fruit is orally administered, 5-(1,4-dihydro-1-methyl-4-oxo-2-quinolin-2-yl) pentanoic acid (EVCA) is excreated as a matabolite in rat urine. In this study, we separated Evodia fruit extract into major alkaloids administered each alkaloid individually to male Wistar rats. Consequently, it was demonstrated that the original substance of the metabolite are evocarpine and its analogues, dihydroevocarpine and 1-methyl-2-undecenyl-4(1H)-quinolone. Investigation of a blood sample after oral administration of evocarpine by high performance liquid chromatography confirmed that the substance was absorbed without alteration. Pharmacokinetics of evocarpine after intravenous injection was expressed in a one-compartment model, showing a linear elimination of plasma evocarpine up to a dosage of 75 mg/kg. Total plasma clearance (CL), volume of distribution (Vd), and half-life (T1/2) of evocarpine were 60 ml/min.kg, 3.21/kg and 0.6 h-1, respectively. Metabolic ratio of evocarpine into EVCA after intravenous injection was 15.4%, and absorption ratio of the unaltered compound calculated from the levels of AUC after oral administration and intravenous injection was 4.7%. In this paper, it is shown that evocarpine is absorbed amount 100% when it is administered orally.     

Liquid chromatography of the potential memory-enhancing agent CL 275,838 and its main metabolites, using a post-column photochemical reactor and fluorimetric detection.

On irradiation with short-wavelength ultraviolet light, the potential memory-enhancing compound CL 275,838 (I) and its desbenzyl derivative CL 286,527 (metabolite II) are cleaved into the highly fluorescent derivative CL 228,346 (metabolite IV). This reaction was exploited for the sensitive and selective detection of these compounds in human and animal plasma, after reversed-phase high-performance liquid chromatography on a Supelco LC18 DB column (15 cm x 4.6 mm I.D.) at room temperature. The parent compound and its metabolites were isolated from plasma constituents using the Sep-Pak C18 Plus cartridge, with satisfactory recovery (76-90%) and selectivity. The detection limits were ca. 1.25, 5 and 0.3 ng/ml for I, II and IV, respectively, using 1 ml of plasma. The validation procedure, which includes analysis of multiple ascending calibration curves based on between-day values and replicate analysis of quality control samples analysed with each standard curve, indicated acceptable precision and accuracy of the method within the concentration ranges investigated, the overall coefficient of variation and relative error being less than 10%. The method was successfully applied to plasma samples from healthy volunteers and animals after single of multiple doses of compound I. Metabolites II and IV were detectable in plasma of all species, the former at higher concentrations than the parent compound and metabolite IV. Together with the fact that metabolite II retains much of the parent compound's biological activity in vivo and in vitro, this suggests that it may contribute to the pharmacological effects of compound I.     

Comparative pharmacokinetics of acetohexamide and its metabolite, hydroxyhexamide in laboratory animals

The pharmacokinetic profiles of the hypoglycemic agent, acetohexamide (AH) and its major active metabolite, hydroxyhexamide (HH) were studied in three species of laboratory animals after intraperitoneal (ipl) administration in comparison with those after intravenous (iv) administration of AH and of the preformed metabolite HH. Reductive biotransformation of AH to HH was reversible in rats and guinea pigs, while it was irreversible in rabbits. The parameters of reversible drug-metabolite pharmacokinetics were calculated, including essential clearances of reversible and irreversible elimination, volumes of distribution at the steady state and sojourn times or turnover rates of the metabolite pair. An interconversion model, which incorporated a first-pass metabolism, was applied to the disposition kinetics of AH and HH, and the available fractions of AH and generated metabolite HH in each species were elucidated.     

Determination of chlorprothixene and its sulfoxide metabolite in plasma by high-performance liquid chromatography with ultraviolet and amperometric detection

This communication describes a rapid, sensitive and selective method for the assay of chlorprothixene and its sulfoxide metabolite in human plasma, using reversed-phase high-performance liquid chromatography. Alkalinized plasma was extracted with heptane--isoamyl alcohol (99:1), after addition of thioridazine as the internal standard. The residue obtained after evaporation of this extract was chromatographed on a cyano column, using acetonitrile--0.02 M potassium dihydrogen phosphate pH 4.5 (60:40) as the mobile phase with ultraviolet (229 nm) detection. Quantitation was based on peak height ratios over the concentration range of 5.0-50.0 ng/ml for both compounds with 85% and 90% recovery for chlorprothixene and its sulfoxide metabolite, respectively, using a 1.0-ml plasma sample. The assay chromatographically resolves chlorprothixene and the sulfoxide metabolite from the N-desmethyl metabolite, which can only be semi-quantitated owing to low and variable recoveries. The method was used to obtain plasma concentration versus time profiles in two subjects after oral administration of 100 mg of chlorprothixene suspension and in two additional subjects following overdosages of chlorprothixene estimated to exceed several hundred milligrams. These analyses demonstrated that the sulfoxide metabolite is the predominant plasma component following therapeutic administration and overdosages. High-performance liquid chromatography with oxidative amperometric detection with the glassy carbon electrode was also evaluated. Although this procedure demonstrated comparable sensitivity and precision to ultraviolet detection for the analysis of chlorprothixene and N-desmethyl chlorprothixene, the sulfoxide metabolite could not be measured with high sensitivity (less than 100 ng/ml) owing to endogenous interferences. Hence the utility of this alternative assay technique is limited.     

Simultaneous determination of etoposide and its catechol metabolite in the plasma of pediatric patients by liquid chromatography/tandem mass spectrometry

The anticancer drug etoposide is associated with leukemias with MLL gene translocations and other translocations as a treatment complication. The genotype of cytochrome P450 3A4 (CYP3A4), which converts etoposide to its catechol metabolite, influences the risk. In order to perform pharmacokinetic studies aimed at further elucidation of the translocation mechanism, we have developed and validated a liquid chromatography/electrospray/tandem mass spectrometry assay for the simultaneous analysis of etoposide and its catechol metabolite in human plasma. The etoposide analog teniposide was used as the internal standard. Liquid chromatography was performed on a YMC ODS-AQ column. Simultaneous determination of etoposide and its catechol metabolite was achieved using a small volume of plasma, so that the method is suitable for pediatric patients. The limits of detection were 200 ng ml(-1) etoposide and 10 ng ml(-1) catechol metabolite in human plasma and 25 ng ml(-1) etoposide and 2.5 ng ml(-1) catechol metabolite in protein-free plasma, respectively. Acceptable precision and accuracy were obtained for concentrations in the calibration curve ranges 0.2--100 microg ml(-1) etoposide and 10--5000 ng ml(-1) catechol metabolite in human plasma. Acceptable precision and accuracy for protein-free human plasma in the range 25--15 000 ng ml(-1) etoposide and 2.5--1500 ng ml(-1) etoposide catechol were also achieved. This method was selective and sensitive enough for the simultaneous quantitation of etoposide and its catechol as a total and protein-free fraction in small plasma volumes from pediatric cancer patients receiving etoposide chemotherapy. A pharmacokinetic model has been developed for future studies in large populations.     

Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice

LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 h). Following intravenous or oral administration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUC_last values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t_1/2 > 1 h) and serum (t_1/2 > 6 h). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.     

Bioavailability studies of oral dosage forms containing levodopa and carbidopa using column-switching chromatography followed by electrochemical detection

A reliable multi-dimensional column chromatographic method employing amperometric detection using a carbon fibre microelectrode procedure was used for monitoring the plasma profiles and to evaluate the pharmacokinetics and bioavailability of levodopa (L-dopa) and carbidopa (C-dopa), after ingestion of oral formulations containing these drugs. The peak currents obtained for the different analytes were directly proportional to the analyte over the concentration range 0.02-4 micrograms ml-1. Using this method, the minimum detectable concentration was estimated to be 5 and 8 ng ml-1 for L-dopa and C-dopa, respectively. Recovery studies ranged from 93.83 to 89.76%, with a relative standard deviation of less than 7%. The study was carried out in two separate weeks on five healthy non-patient fasted male/female volunteers in the age range 20-37 years and weighing between 60 kg and 78 kg. The pharmacokinetic profile of two controlled-release products containing both L-dopa and C-dopa (Sinemet CR3 and CR4) was compared on the one hand and Sinemet conventional tablets on the other. The pharmacokinetic parameters, peak concentration (Cmax), the time taken to obtain this level (Tmax), elimination half-time T1/2, elimination rate constant (Kel), plasma level ratio, fluctuation index (FI) and the area under the time-concentration curve (AUC0-8), were investigated for each individual formulation. A comparison of the uptake of L-dopa from the conventional formulation showed that L-dopa entered the plasma and achieved peak levels higher than that of the controlled release formulations. However, it showed a much higher fluctuation index and the plasma concentrations were more stable with the controlled release formulations. The data also indicated a very low accumulation of both levodopa and carbidopa following repeated administration of the drugs, which was consistent with their relatively short half-lives (less than 2 h). In contrast, the half-life for the metabolite 3-orthomethyl dopa (3-OMD) is in the order of 13 h. As a result, there was an extensive accumulation of 3-OMD and its levels were significantly higher than those of levodopa or carbidopa upon repeated administration. Urine recoveries of the three analytes over one 8 h dosing interval showed that the majority of the excreted levodopa and carbidopa was recovered during the first 4 h, and there is proportionally greater excretion of the carbidopa dose than the levodopa dose.     

Lansoprazole‐sulfide,pharmacokinetics of this promising anti‐tuberculous agent

Lansoprazole (LPZ) is a commercially available proton‐pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis . It was also reported that a 300 mg kg⁻¹ oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography–tandem mass spectrometric method (LC–MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg⁻¹ oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL⁻¹, respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti‐TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti‐TB compound.     

Urinary metabolic profile of 19-norsteroids in humans: glucuronide and sulphate conjugates after oral administration of 19-nor-4-androstenediol

19-Nor-4-androstenediol (NOL) is a prohormone of nandrolone (ND). Both substances are included in the WADA List of Prohibited Classes of Substances and their administration is determined by the presence of 19-norandrosterone (NA) with the urinary threshold concentration of 2 ng mL(-1). Routine analytical procedures allow the determination of NA excreted free and conjugated with glucuronic acid, but amounts of ND and NOL metabolites are also excreted in the sulphate fraction. The aim of this study is to determine the urinary metabolic profile after oral administration of a nutritional supplement containing NOL. Urine samples were collected up to 96 h following supplement administration and were extracted to obtain separately three metabolic fractions: free, glucuronide and sulphate. Extraction with tert-butyl methyl ether was performed after the hydrolysis steps and trimethylsilyl derivatives were analyzed by gas chromatography/mass spectrometry (GC/MS). After oral administration of NOL, the main metabolites detected were NA and noretiocholanolone (NE) in the glucuronide and sulphate fractions. The relative abundances of each metabolite in each fraction fluctuate with time; a few hours after administration the main metabolite was NA glucuronide whereas in the last sample (4 days after administration) the main metabolite was the NA sulphate and the second was the NE glucuronide. During the studied period almost half of the dose was excreted and the main metabolites were still found in urine after 96 h. Norepiandrosterone and norepietiocholanolone were also detected only in the sulphate fraction. Our results suggest that sulphate metabolites should be taken into consideration in order to increase the retrospectivity in the detection of 19-norsteroids after oral administration. Copyright (c) 2008 John Wiley & Sons, Ltd.     

High-performance liquid chromatographic method for the determination of a potential memory-enhancing compound (CL 275,838) and its desbenzyl metabolite in rat plasma or serum.

A rapid, selective, precise reversed-phase liquid chromatographic method has been developed for the determination of a potential memory-enhancing agent (CL 275,838) and its main metabolite (CL 286,527) in plasma and serum. The procedure includes isolation of compounds from proteins precipitated with acetonitrile, subsequent resolution by reversed-phase (Whatman Partisphere C8) high-performance liquid chromatography and ultraviolet detection. The assay was linear over the range 0.12-1.25 micrograms/ml of plasma or serum. The detection limit was 0.12 micrograms/ml, using 0.2 ml of plasma or serum. Intra- and inter-day validation studies indicated an acceptable precision and reproducibility of the method within the concentration range investigated, the overall coefficient of variation being less than 10%. The method is currently applied in support of pharmacological and toxicity studies of the compound in rodents.     

Design of polyvinyl alcohol hydrogel as a controlled-release vehicle for rectal administration of dl-propranolol-HCl and atenolol

Preparations of beta-blockers, propranolol-HCl and atenolol, in poly(vinyl alcohol) (PVA) hydrogel were designed for the therapeutic treatment of hypertension by transrectal delivery. In vitro release characteristics and plasma drug concentration profiles after rectal administration in rats and dogs were examined. The PVA hydrogels containing beta-blockers were prepared by a low-temperature crystallization method. The release of beta-blockers from hydrogel preparations was consistent with Fickian diffusion (Higuchi model); the drug release versus the square root of release time profile gave a straight line over 60% of the total release process. The release of beta-blockers from hydrogel preparations increased at higher concentrations of PVA in the hydrogel preparations and was not affected by the pH of hydrogel preparations. Plasma concentrations of beta-blockers after rectal administration of hydrogels were higher than those after administration of suppositories (Witepsol H-15) in rats and dogs. The drug plasma concentrations increased at higher concentrations of PVA in hydrogel preparations. In the case of propranolol, which is a hepatic high-clearance drug, area under the blood concentration curve, 0-8 h after rectal administration of a hydrogel preparation (20% w/w PVA, pH 7.0) was 2.16 times and 5.26 times higher than those obtained with Witepsol H-15 suppository and oral administration, respectively. Rectal administration with PVA hydrogels is a favorable route for a hepatic high-clearance drug such as propranolol.     

Glutathione and methylation of inorganic arsenic in hamsters

The effect of giutathione (GSH) concentrations in livers and kidneys of hamsters on the toxicity and methylation of arsenite in these animals was studied. No significant changes in hepatic and renal GSH concentrations were observed after a single arsenite administration (5 mg As kg^?1, p.o.). When buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, was given (4 mmol kg^?1, i.p.) two hours before administration of arsenite, hepatic and renal GSH concentrations were more severely and persistently depressed than in the case of BSO administration not followed by arsenite. Hamsters treated with BSO plus arsenite suffered from severe nephrotoxicity (acute renal failure) characterized by increases in plasma creatinine and urea nitrogen and by proximal tubular necrosis. Concurrently, transient hepatotoxicity was observed in the BSO plus arsenite group. Neither arsenite alone nor BSO alone produced liver or kidney injury. The BSO plus arsenite-treated animals excreted in the urine only 3.5% of the arsenic dose during the 72 h period after administration of arsenite, probably because of a decrease in urine volume caused by kidney injury, whereas the arsenite-only group excreted 27%. In addition, BSO pretreatment influenced the relative proportion of arsenic metabolites excreted in the urine during the first 24 h after administration. Urinary metabolites in the BSO plus arsenite group were predominantly inorganic arsenic. These results suggest that GSH provides protection against arsenic toxicity.     

Effect of pulverization of the bulk powder on the hydration of creatine anhydrate tablets and their pharmaceutical properties

The hydration behavior and expansion properties of untreated and pulverized creatine anhydrate (CRA) tablets were studied under 60 and 75%RH at 25 degrees C by using differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). The tablet hardness of untreated and pulverized CRA tablets was significantly decreased after hydration. There was a linear relationship between the degree of hydration and the tablet hardness of untreated CRA tablets compressed at 1000 kg/cm2. In contrast, the relationship between the degree of hydration and the tablet hardness of pulverized CRA tablets was nonlinear. These results suggest that the reduction in hardness of pulverized CRA tablets does not depend solely on the hydration level of crystal water. PXRD analysis indicated that the diffraction pattern of the pulverized CRA powder was similar to that of the untreated CRA powder. However, the diffraction intensity of the pulverized CRA powder was slightly lower than that of the untreated CRA powder at high angle. The micropore radius of both untreated and pulverized CRA tablets was significantly increased after hydration, but analysis of the relationship between micropore radius and fractional hydration of crystal water showed that untreated CRA tablets were more affected than pulverized CRA tablets. Therefore, the reduction in tablet hardness depends not only on the hydration behavior but also on the crystal orientation of the CRA powder.     

Interspecies differences in pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl) benzimidazole difumarate (KG-2413) after intravenous administration to rats, guinea pigs and dogs

Interspecies differences in the pharmacokinetics of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1,4-diazepin-1-yl)benzimid azole difumarate (KG-2413) after intravenous administration were investigated in rats, guinea pigs and dogs. The disappearance of unchanged KG-2413 base was described by biexponential curves in all three animal species. The areas under the plasma concentration-time curves (AUC) in rats, guinea pigs and dogs were 218, 421 and 369 ng.h/ml, respectively, at a dose of 2 mg/kg. The volume of distribution in rats was comparable to that in dogs, and was about three times greater than that in guinea pigs. This might be due to the difference in the unbound fractions of KG-2413 base in plasma (fu), that is, the values of fu in rats, dogs and guinea pigs were 0.607, 0.603 and 0.189, respectively. The first-order elimination rate constant from the central compartment (kcl) in dogs were smaller than those in rats and guinea pigs. Total body clearances (CLtot) of KG-2413 base in rats and guinea pigs were comparable to the hepatic blood flow rate (Q) of each animal. Assuming that KG-2413 base is only eliminated in the liver, relatively rapid metabolism of KG-2413 base occurred in the liver of rats and guinea pigs. In dogs, extrahepatic elimination was suggested because the value of CLtot seemed to be greater than that of Q.     

Determination of benperidol and its reduced metabolite in human plasma by high-performance liquid chromatography and electrochemical detection

An isocratic high-performance liquid chromatographic method with electrochemical detection for the quantification of benperidol and its suggested reduced metabolite TVX Q 5402 in human plasma is described. The method included a two-step solid-phase extraction on reversed-phase and cation-exchange material, followed by separation on a cyanopropyl silica gel column (5 microns; 250 mm x 4.6 mm I.D.). The eluent was 0.15 M acetate buffer (pH 4.7) containing 25% acetonitrile (w/w). Spiperone served as internal standard. The inclusion of the cation-exchange step provided sample purity higher than those achieved with other methods. After extraction of 1 ml of plasma, concentrations as low as 0.5 ng/ml were detectable for both benperidol and the metabolite. In plasma samples collected from a schizophrenic patient treated with a single oral dose of 6 mg of benperidol, plasma levels of benperidol and of the metabolite could be measured from 20 min to at least 12 h after administration.     

Reversed-phase liquid chromatographic determination of plasma levels of adriamycin and adriamycinol

A method is given for the determination of adriamycin and its main metabolite, adriamycinol in plasma from cancer patients after administration of adriamycin as the free drug or as a complex with DNA. Adriamycin and adriamycinol are extracted in a column from 1 ml of plasma (pH 8.6) using a mixture of chloroform--1-heptanol (8:2). After re-extraction into phosphate buffer pH 2.2, the separation is performed as reversed-phase liquid chromatography on a LiChrosorb RP-2 (5 micron) column with a mobile phase of acetonitrile-water, acidified with phosphoric acid. The precision by quantitation with photometric detection was better than 5% within the range 50-300 ng/ml. Plasma levels of adriamycin and adriamycinol in a cancer patient are presented in this paper.     

Thermal and electronic charge transport in bulk nanostructured Zr0.25Hf0.75NiSn composites with full-Heusler inclusions

Bulk Zr_0.25Hf₀₇₅NiSn half-Heusler (HH) nanocomposites containing various mole fractions of full-Heusler (FH) inclusions were prepared by solid state reaction of pre-synthesized HH alloy with elemental Ni at 1073 K. The microstructures of spark plasma sintered specimens of the HH/FH nanocomposites were investigated using transmission electron microscopy and their thermoelectric properties were measured from 300 K to 775 K. The formation of coherent FH inclusions into the HH matrix arises from solid-state Ni diffusion into vacant sites of the HH structure. HH(1–y)/FH(y) composites with mole fraction of FH inclusions below the percolation threshold, y∼0.2, show increased electrical conductivity, reduced Seebeck coefficient and increased total thermal conductivity arising from gradual increase in the carrier concentration for composites. A drastic reduction (∼55%) in κ_l was observed for the composite with y=0.6 and is attributed to enhanced phonon scattering due to mass fluctuations between FH and HH, and high density of HH/FH interfaces.     

Analysis of 2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(3-iodo-E-allyl)nortropane in rat plasma. II. Pharmacokinetic profile in male and female Sprague-Dawley rats evaluated by capillary electrophoresis

This paper describes a pharmacokinetic study performed in Sprague-Dawley rats after i.v. administration of a single 6-mg/kg dose of 2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(3-iodo-E-allyl)nortropane (Altropane). Plasma samples were collected from the retro-orbital sinus at times up to 3 h after drug administration, extracted by solid-phase extraction, and the drug levels determined by capillary electrophoresis (CE). Pharmacokinetic parameters were determined by a standard noncompartmental model using WinNonlin version 1.5. The maximum plasma concentrations, clearances of the drug, and areas under the curve for male and female rats were 5.74 and 7.26 microg/ml, 135.7 and 98.5 ml/kg x min, and 44.23 and 60.92 microg x min/ml, respectively. The drug was cleared very rapidly from the systemic circulation, with a terminal t(1/2) of 7 to 10 min and a mean residence time of about 11 min for both sexes. The volume of distribution was approximately 1 l/kg. No metabolites were detected when the samples were analyzed individually. However, after samples were pooled and concentrated, traces of two unknown peaks that may represent metabolites were detected in concentrates from the last two timepoints. Part I of this work [J. Chromatogr. A, 895 (2000) 87] describes validation of CE methods for the analysis of aqueous and plasma samples of Altropane, including its solid-phase extraction from rat plasma.