Enantioselective pharmacokinetics of lercanidipine in healthy volunteers

OBJECTIVE: The enantioselective kinetic disposition of lercanidipine, a dihydropyridine type of third-generation calcium antagonist, was investigated in six healthy male volunteers following a single 20 mg racemic oral dose. METHODS: Serial plasma samples were obtained from 0 to 24 h after drug administration. Lercanidipine enantiomers were analysed using a chiral LC-MS-MS method. RESULTS: The following differences (p < 0.05, Wilcoxon test) between (S) and (R) enantiomers were found (median): C(max) 2.071 ng mL(-1) versus 1.681 ng mL(-1); AUC(0-24)12.352 ng h mL(-1) versus 10.063 ng h mL(-1) and Cl/f 732.16 L h(-1) versus 1891.84 L h(-1). The AUC(0-infinity) values for (S)-LER were 1.21-fold higher than those for (R)-LER. CONCLUSION: The pharmacokinetics of LER was enantioselective in healthy volunteers following a single dose of 20 mg of the unlabeled racemic drug.     

Tissue distribution of ibogaine after intraperitoneal and subcutaneous administration

The distribution of the putative anti-addictive substance ibogaine was measured in plasma, brain, kidney, liver and fat after ip and sc administration in rats. One hr after ip dosing (40 mg/kg), drug levels ranged from 106 ng/ml (plasma) to 11,308 ng/g (fat), with significantly higher values after sc administration of the same dose. Drug levels were 10–20 fold lower 12 hr after the same dose. These results suggest that: 1) ibogaine is subject to a substantial “first pass” effect after ip dosing, demonstrated by higher drug levels following the sc route, 2) ibogaine shows a large accumulation in adipose tissue, consistent with its lipophilic nature, and 3) persistence of the drug in fat may contribute to a long duration of action.     

Pharmacokinetic profile of (+/-)-gossypol in male Sprague-Dawley rats following single intravenous and oral and subchronic oral administration

The pharmacokinetic profile of (+/-)-gossypol was determined in male Sprague-Dawley rats following a single intravenous or oral 10 mg/kg dose and after receiving a daily oral 10 mg/kg dose for 14 days. The intravenous plasma (+/-)-gossypol level data were fitted with a three-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous administration was 11.44 hr, corresponding to an elimination rate constant of 0.05 hr-1. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma following a single intravenous administration were 0.16 liter/hr/kg, 0.05 liter/kg, and 63.09 mg.hr/liter, respectively. The bioavailability of a single oral dose of (+/-)-gossypol in rats was 60%. The change in plasma (+/-)-gossypol concentration after a single or after multiple doses showed a biphasic pattern. A single oral dose of (+/-)-gossypol, however, was eliminated five times faster than the daily administered chemical. Thus, a single oral dose of (+/-)-gossypol was eliminated at a rate constant of 0.01 hr-1, corresponding to half-life of 64.76 hr. Subchronic oral administration of (+/-)-gossypol showed an apparent half-life of 101.91 hr-1, corresponding to a rate constant of 0.007 hr-1. The results indicate that multiple oral dosing of (+/-)-gossypol resulted in its longer retention in body tissue than a single oral dose. This study suggests that pharmacokinetics of (+/-)-gossypol may play, at least in part, a role in the reproductive toxicity of subchronic but not single oral dosing.     

Pharmacokinetics of the beta-carboline norharman in man.

In healthy subjects, pharmacokinetics were characterised using single oral and sublingual administrations of the beta-carboline norharman. For this purpose, norharman levels in blood plasma were measured up to 90-105 min after both routes of administration. Dose proportionality of three different single oral doses of norharman (7, 65 and 110 microg/kg) administered as 0.52 and 5 mg capsules was evaluated at 8 time points. Peak levels were attained at 30 min after the oral load of norharman. Mean relative availabilities determined by the area under the curve (AUC) procedure were 14.3 and 98.0 nmol.min/l after oral dosing of 7 and 65 microg/kg, respectively. AUC values in women were 3-4 times higher than in men. Sublingual dosing of 6.5 and 13 microg/kg norharman encapsulated in 5 mg of cyclodextrins resulted in a much higher mean AUC and a more rapid absorption. Mean AUC after sublingual administration of 6.5 microg/kg was 929.8 nmol.min/kg and plasma levels were maximal 10-15 min after norharman was given. Moreover, apparently no sex difference was found using this way of application. Norharman disappeared from the plasma with half-lifes of 25-35 min, irrespective of the route of administration. Even at the highest measured norharman levels of 53 nmol/l plasma, no behavioral effects were observed. In addition, the subjects did neither report any effects nor any side-effects during the experiment. This is the first study in which the kinetics of ingested norharman have been measured in humans.     

Comparative measurement of spinal CSF microdialysate concentrations and concomitant antinociception of morphine and morphine-6beta-glucuronide in rats

Morphine-6beta-glucuronide (M6G) is well known as a potent active metabolite in humans. To clarify concentration-antinociceptive effect relationships for morphine and M6G, we evaluated comparatively the pharmacokinetics and antinociceptive effects of morphine and M6G. The spinal CSF concentration and antinociception were simultaneously measured by using the combination of a microdialysis method and the formalin test in conscious rats after the s.c. administration of morphine (0.3-3 mg/kg) and M6G (0.1-3 mg/kg). The plasma concentration of M6G after s.c. administration was higher than that of morphine, as shown by the 2.1 times greater value of area under the concentration-time curve (AUC(plasma)). The spinal CSF concentrations of morphine and M6G increased dose-dependently. The AUC(CSF) of M6G was 1.6-1.8 times higher than that of morphine at each dose. Administration of morphine and M6G dose-dependently suppressed the flinching behavior induced by formalin injection. The ED(50) values for M6G were 3 times lower than those of morphine, although the spinal CSF concentration versus antinociceptive effect curves of morphine and M6G were very similar, with similar EC(50) values. These results suggest that the antinociceptive potencies of morphine and M6G, evaluated by simultaneous measurements of spinal CSF drug concentration and antinociception, are equivalent. Simultaneous measurement of spinal CSF concentration and antinociception by using microdialysis should be useful for elucidating the relationship between pharmacokinetics and pharmacodynamics of various opioids.     

Mammalian blood-mediated mutagenicity tests using a multipurpose strain of Escherichia coli K-12

Cytogenetic studies have been performed to determine the effect of 6-mercaptopurine (6-MP) on mammalian chromosomes in vivo. An elevated level of chromosome breakage is present in mouse bone marrow cells within 12 h after oral or parenteral dosing with 200 mg/kg. Damage is most severe at 24 h after oral dosing and at 72 h following intraperitoneal injection. A dose-response curve was constructed using oral doses of 10 to 200 mg/kg. The no-effect dose level lies within the 10–25 mg/kg range when administered as a single dose. In subacute studies, positive results have been obtained with as little as 2.5 mg/kg/day administered orally for 5 days.     

Pharmacokinetics of reboxetine enantiomers in the dog

Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean t_max was about 1 h for both enantiomers. C_max and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values ± SD being 704 ± 330 and 427 ± 175 ng/ml for C_max and 2,876 ± 1,354 and 1,998 ± 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t½ (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0–48 h) being 1.3 ± 0.7 and 1.1 ± 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans. Chirality 9:303–306, 1997. © 1997 Wiley-Liss, Inc.     

Enantioselective Pharmacokinetics of Doxazosin and Pharmacokinetic Interaction Between the Isomers in Rats

In this study, the stereoselective pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high‐pressure liquid chromatography (HPLC) with fluorescence detection after oral or intravenous administration of (–)‐(R)‐doxazosin 3.0 mg/kg, (+)‐(S)‐doxazosin 3.0 mg/kg, and rac‐doxazosin 6.0 mg/kg. AUC values of (+)‐(S)‐doxazosin were always larger than those of (–)‐(R)‐doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (C_max) value of (–)‐(R)‐doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the C_max value of (+)‐(S)‐doxazosin did not change significantly. The area under the curve (AUC) and C_max values for (+)‐(S)‐doxazosin after intravenous administration were significantly lower, and its Cl value significantly higher, when given alone versus in racemate. We speculate that (–)‐(R)‐doxazosin increases (+)‐(S)‐doxazosin exposure probably by inhibiting the elimination of (+)‐(S)‐doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer–enantiomer interaction occurs after rac‐administration. Chirality 27:738–744, 2015. © 2015 Wiley Periodicals, Inc.     

Influence of Dose and Route of Administration on the Enantioselective Pharmacokinetics of TJ0711 Hydrochloride in Rats

The enantioselective pharmacokinetics of TJ0711 hydrochloride were studied in rats given different doses of rac‐TJ0711 hydrochloride via intravenous and oral routes. R‐ and S‐TJ0711 hydrochloride were both rapidly absorbed, and the average AUC_0‐∞ of R‐TJ0711 hydrochloride was greater than that of S‐TJ0711 hydrochloride after intragastric administration, with an R/S AUC ratio 1.11 and 1.35 for 30 and 50 mg/kg dose group, respectively. In contrast, the average AUC_0‐∞ of R‐TJ0711 hydrochloride was smaller than that of S‐TJ0711 hydrochloride after intravenous injection, with an R/S AUC ratio 0.57 and 0.73 for 10 and 20 mg/kg dose group, respectively. R‐TJ0711 hydrochloride plasma half‐lives were shorter than those of S‐TJ0711 hydrochloride for all groups. AUC_0‐4h and C_max between the two enantiomers were significantly different after oral administration of 50 mg/kg dose of the racemate, while no significant differences between the two enantiomers were found for all the pharmacokinetic parameters of the 30 mg/kg dose group. Significant differences between the two enantiomers were detected for nearly all the pharmacokinetic parameters after intravenous administration, except for the V_Z of 20 mg/kg dose group. This study suggests that dose and route of administration will influence the enantioselectivity in the pharmacokinetics of TJ0711 hydrochloride in rats. Chirality 27:53–57, 2015. © 2014 Wiley Periodicals, Inc.     

Pharmacokinetics of iloprost and cicaprost in mice.

Iloprost and cicaprost are two PGI2-mimetics, which are chemically stable and highly pharmacologically potent. Both compounds differ by their susceptibility to metabolic degradation. While iloprost contains a pentanoic acid upper side chain, which is subject to beta-oxidative degradation, cicaprost is metabolically stabilized by the introduction of an oxygen atom at position 3 of the pentanoic acid chain, preventing beta-oxidation. Both compounds have been characterized concerning their pharmacological and pharmacokinetic profile in a number of animal species and in man. In the present set of experiments both drugs were characterized in terms of pharmacokinetics in mice, an animal species quite routinely used in long-term toxicity studies on cancerogenicity, by iv and ig administration of 0.2 mg/kg (iloprost) and 0.01 mg/kg (cicaprost) using tritiated substances. Iloprost was rapidly inactivated after iv dosing with plasma levels declining from 247 to 0.27 ng/ml within 60 min. Disposition half-lives were 3 and 14 min. Total clerance accounted for 152 ml/min/kg. Total radiolabel exhibited a clearance of 35 ml/min/kg, its AUC in plasma was 146 ng-equiv.h/ml. After ig administration Iloprost peak plasma levels of 9.2 ng/ml occurred after 5 min. Bioavailability was 10%. AUC of total radiolabel was 152 ng-equiv.h/ml, showing complete absorption. Excretion of 3H-label was 41%/57% of dose (iv) and 36%/47% o.d. (ig) with the urine and 32%/18% o.d. (iv) and 36%/25% o.d. (ig) in male/female animals and proceeded for > 90% of dose fraction recovered with half-lives of 0.2-0.3 d. Metabolic patterns revealed the known profile consisting of unchanged drug, dinor- and tetranor-metabolites in plasma and mainly, tetranor-products in urine and feces. After iv dosing of cicaprost total radiolabel plasma levels declined biphasically with half-lives of approx. 0.05 h and 0.31 h. Extrapolated AUC was 1.6 ng-equiv. h/ml and total clearance accounted for 108 ml/min/kg. After ig treatment peak radioactivity plasma levels of 0.7 and 1 ng-equiv./ml were observed at 0.16 and 1 h postdose, probably due to differences between animal groups. Extrapolated AUC was 1 ng-equiv.h/ml. Excretion of 3H-label was mainly biliary: With the feces 83%/89% o.d. (iv) and 93%/92% o.d. (ig) were excreted by male/female animals, while 8.3%/5.7% o.d. (iv) and 2.6%/5.5% were recovered in the urine. More than 90% of the excreted radiolabel was found in samples collected up to 24 h postdose. Metabolic patterns in plasma revealed that after both routes of administration 3H-cicaprost was the dominant radiolabel fraction accounting for up to 90% of total radiolabel chromatographed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evaluation of the genotoxicity of the imidazole antifungal climbazole: comparison to published results for other azole compounds

Climbazole is an imidazole antifungal agent that can provide anti-dandruff benefits when incorporated into a shampoo matrix. A series of genotoxicity studies were performed to support the human safety of this azole antifungal drug. Climbazole was not mutagenic in the Salmonella typhimurium or Escherichia coli Ames assay and did not induce micronuclei in human lymphocytes. In the mouse lymphoma assay (MLA), climbazole was negative (non-mutagenic) with and without metabolic (S9) activation after a 4 h exposure; an increase in small colony mutants was observed without metabolic activation after a 24 h exposure at concentrations of 15 and 17.5 μg/mL. An in vivo mouse micronucleus test was negative up to a maximum tolerated dose (MTD) of 150 mg/kg climbazole administered orally. In the in vivo/in vitro unscheduled DNA synthesis assay, climbazole showed no evidence of DNA damage in the livers of rats at doses up to the MTD of 200 mg/kg orally. A toxicokinetic study was performed in mice with oral administration of [14C]-climbazole (150 mg/kg). Radioactivity (20.42 μg-equiv./g plasma) was detected 15 min after oral administration of [14C]-climbazole, and the peak concentration was 62.96 μg-equiv./g plasma at 8 h after dosing. The measured amounts of radioactivity in plasma, at all sample times from 15 min up to 24 h, exceeded the concentrations that induced increases in mutation frequency after 24 h exposure of mouse lymphoma cells in vitro (15 and 17.5 μg/mL). These observations lend support to the conclusion that climbazole does not present a genotoxic risk in vivo. Furthermore, these data are consistent with the published data for other azole antifungals that work by preventing the synthesis of ergosterol and, as a class, are generally non-genotoxic, except some isolated positive results of questionable significance. Collectively, these data are supportive of the view that climbazole does not present a genotoxic or carcinogenic risk to humans.     

Stereoselective pharmacokinetics of indobufen from tablets and intramuscular injections in man

The influence of administration route (oral or intramuscular (i.m.)) on the pharmacokinetics of total indobufen (INDB) enantiomers was studied in healthy volunteers after a 200 mg dose as a single oral tablet or i.m. injection. Enantiospecific reversed phase (RP) HPLC with UV detection was used for the determination of INDB enantiomers in serum. INDB enantiomers were isolated from serum by solid phase extraction (SPE) procedure using C(18) columns. INDB enantiomers were converted to their L-leucinamide diastereoisomers and separated on a C(18) HPLC column. INDB from i.m. injections is absorbed faster (t(max) = 0.6-0.9 h) than from tablets (t(max) = 1.3-1.8 h). The area under curve (AUC) after administration of the tablet was slightly higher than after i.m. injection. The pharmacokinetic behaviour of (+)-S- and (-)-R-INDB after administration of the tablet was different from i.m. injection of racemic INDB. The (+)-S-enantiomer is more rapidly eliminated than its (-)-R-antipode. Statistically significant differences also occurred between enantiomers in AUC, first order elimination rate constant (k), clearance (Cl). The ratio AUC(R):AUC(S) was similar for the tablet (1.57-1.62) and i.m. injection (1.59-1.62). It was concluded that the formulation and extent of ionisation of rac-INDB (acid or sodium salt of INDB) do not significantly influence its stereoselective pharmacokinetics.     

Toxicity and pathological effects of orally and intraperitoneally administered ivermectin on sea bass Dicentrarchus labrax

The toxicity and histopathology of ivermectin was studied in 3 and 35 g sea bass Dicentrarchus labrax L. following in-feed, oral intubation and injection administration at dose rates ranging from 0.5 to 3.5 mg kg(-1). Estimated LD50 values for 3 g fish were 0.335 and 0.106 mg kg(-1) following oral intubation and injection administration respectively, for fish reared at 11 degrees C; and 0.839 and 1.023 mg kg(-1) following oral intubation and injection administration, respectively for fish reared at 20 degrees C. For 35 g fish reared at 11 degrees C, the estimated LD50 was 0.523 and 0.361 mg kg(-1) following oral intubation and injection administration respectively. No signs of toxicity were observed when the compound was administered via the feed at 0.5 and 0.7 mg kg(-1). However, toxicity (> 10%) was observed at dose rates of 0.2 mg kg(-1) and higher when the compound was administered via oral intubation and at 0.5 mg kg(-1) when administered via injection. The compound was significantly more toxic to fish reared at 11 degrees C than at 20 degrees C. Further, ivermectin was more toxic to 3 g than to 35 g sea bass when administered via injection. Histopathological examination of the major organs revealed pathology was largely restricted to gills and intestinal tissue. In 3 g sea bass, lesions were also found in the kidneys.     

N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

Glucagon-like peptide-1(7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH(2)-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH(2)-terminally modified His(7)99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His(7)-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691+/-35 mM/min) was significantly lower after administration of tGLP-1 and His(7)-glucitol tGLP-1 (36 and 49% less; AUC 440+/-40 and 353+/-31 mM/min, respectively; P<0.01). This was associated with a significantly higher AUC for insulin (98-99% greater; AUC 834+/-46 and 838+/-39 ng/ml/min, respectively; P<0.01) after tGLP-1 and His(7)-glucitol tGLP-1 administration compared to controls (421+/-30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo.     

Fetal and maternal tissue distribution of the new fluoroquinolone DW-116 in pregnant rats

We investigated maternal and fetal tissue distribution of DW-116, a newly developed fluoroquinolone with a broad antibacterial spectrum against both G(+) and G(-) bacteria, in pregnant rats. After oral administration of [14C]-DW-116 (labeled 1 mg and unlabeled 500 mg/kg) to female rats on the 18th day of gestational, groups of three rats were killed at various time points up to 24 h, and plasma and tissues were collected, processed and analyzed. [14C]-DW-116 was rapidly absorbed, and distributed into the maternal and fetal tissues, and it declined in a biphasic manner with elimination half-lives (t(1/2)) of 10-15 h and mean residence times (MRT(0-24 h)) of 4-9 h. The radioactivity in most tissues of both dams and fetus reached its peak within 1 h and radioactivity levels of up to 10-25% of the peak level were maintained until 24 h after dosing. Among various tissues, the radioactivity in the maternal lungs was the highest (27 times that of plasma) at the C(max). Radioactivity in other tissues including liver, kidney, heart, lung, brain, spleen, mammary gland, placenta, ovary and uterus was higher than that in the maternal plasma (one- to three-fold). The tissue-to-plasma partition coefficient (K(p), AUC(0-24 h,tissue)/AUC(0-24 h,plasma)) of [14C]-DW-116 in maternal tissues was highest in the lung (K(p)=3.7), followed by the spleen (2.2), kidney (2.0), liver (1.8), heart (1.5), placenta (1.3), brain (1.3), ovary (1.1), uterus (1.1), and mammary gland (1.0). The tissue-to-plasma partition coefficient values in fetal tissues were heart (K(p)=2.2), kidney (2.1), liver (1.9), lung (1.6) and brain (1.4). When lactating rats were given a single oral dose of [14C]-DW-116, the radioactivity was rapidly secreted into the milk with K(p) of 1.7 at T(max) (0.5 h). These results indicate that DW-116 or its related metabolite(s) rapidly cross the blood-placenta and blood-milk barrier, extensively distribute into the fetal tissues, and are eliminated from the body in a prolonged manner. This study sheds insights into the maternal and fetal tissue distribution of DW-116 and will be useful for assessing both therapeutic and toxicological relevance of DW-116 in pregnant subjects.     

Pharmacokinetic and tissue distribution study of [14C]fluasterone in male Beagle dogs following intravenous,oral and subcutaneous dosing routes

The purpose of this work was to compare the pharmacokinetics (PK) and tissue distribution of [¹⁴C]fluasterone following intravenous (iv), subcutaneous (sc) and oral (po) administration in male Beagle dogs. The main goal of the investigation was to discover if non-oral routes would alter parameters observed in this study following the administration of [¹⁴C]fluasterone. The oral formulation had a lower bioavailability (47%) compared to the sc formulation (84%). Po and sc administration resulted in a similar t_max; however, the observed C_max following sc dosing was less than half of that after oral dosing. The sc route had the greatest overall exposure (AUC_0–∞). Tissue distribution analysis 2 h post-intravenous dosing showed that connective tissue (adipose and bone), liver, and skeletal muscle accumulated relatively high levels of fluasterone. The majority of the dose was retained during the first 24 h. Elimination of [¹⁴C]fluasterone-derived radioactivity following intravenous dosing resulted in urine and feces containing 7.6% and 28%, respectively, of the total dose over the first 24 h. Elimination of [¹⁴C]fluasterone-derived radioactivity following subcutaneous dosing resulted in 4.6% in urine and 7.8% in feces of the total dose over the first 24 h. Following oral dosing, elimination resulted in 3.8% in urine and 36% in feces over the first 24 h. In conclusion, the sc route of administration offers some advantages to po and iv due to the prolonged release and increased retention through 24 h.     

In vivo covalent binding of [14C]trinitrotoluene to proteins in the rat.

When a single dose of [14C]trinitrotoluene was administered intraperitoneally (i.p.) to rats at 1, 10 or 50 mg/kg of body weight, covalently bound radioactivity was detected in globin, plasma proteins and proteins in the liver and kidney. The extent of covalent binding was dose dependent and was highest in plasma and renal proteins at all times up to 4 h after dosing. Covalent adduct levels in globin, however, decline slower than others. At a dose of 50 mg/kg of body weight, globin covalent adduct levels peaked at 1 h after dosing at 182 pmol/mg protein and subsequently decreased to approximately 50 pmol/mg protein between days 1 and 8. Of the covalent adduct levels in liver and kidney, those in the 10,000 x g and microsomal fractions were found to be higher than that in the cytosolic fraction. Radioactivity covalently bound to globin and the hepatic proteins was susceptible to dilute acid hydrolysis from which 2-amino-4,6-dinitrotoluene (2A) and 4-amino 2,6-dinitrotoluene (4A) were the major products recovered by solvent extraction. Upon acetylation, the hydrolysate gave rise to derivatives identified as the acetates of 2A and 4A on the basis of mass spectrometry and HPLC cochromatography with authentic samples. Four hours after an i.p. dose of [14C]TNT at 50 mg/kg of body weight about 0.4% of the dose was found as bound adducts to hemoglobin, of which approximately 48% was recovered as solvent extractable radioactivity after acid hydrolysis. About 2% of the radioactive dose was in the liver, of which approximately 30% was covalently bound to hepatic proteins, and approximately 49% of that was convertible to solvent extractable radioactivity upon acid hydrolysis. In vitro incubation of [14C]TNT with blood showed that there was a linear increase of covalent adducts in globin during the first 2 h of incubation; the concentration of covalent adducts was slightly higher than that with plasma proteins. The major compounds recovered from the hydrolysate of the globin adducts were also 2A and 4A as obtained from globin in the in vivo studies. On the basis of the in vitro and in vivo study results, we have confirmed the formation of protein adducts following a single i.p. administration of [14C]TNT at 1, 10 or 50 mg/kg of body weight to the rat or by in vitro incubation with blood.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of the pharmacokinetics of subcutaneous and intravenous administration of a phosphorothioate oligodeoxynucleotide in cynomolgus monkeys

The pharmacokinetics of subcutaneous (s.c.) administration of a phosphorothioate oligodeoxynucleotide (PS-ODN) was evaluated in cynomolgus monkeys. In a single dose study, monkeys were injected s.c. or intravenously (i.v.) with doses of either 1 or 5 mg/kg ISIS 2302. The bioavailability of s.c. injection ranged from 26% to 55% and appeared to be dependent on the concentration of the dosing solution rather than the dose. The bioavailability of a subcutaneously administered 5 mg/kg dose of ISIS 2302 was 55% using a 50 mg/ml dosing solution and only 26% using a 10 mg/ml dosing solution. Slow absorption from the s.c. injection site significantly blunted the maximal concentration (Cmax) compared with i.v. administration. The time to peak plasma concentration (Tmax) increased slightly with increasing dose, from 0.5 to 1 hour for the 1 mg/kg dose to 1 to 2.5 hours for the 5 mg/kg dose. Plasma half-lives were prolonged after s.c. administration, indicating more dependence on absorption than elimination. The half-lives after s.c. administration averaged 3 hours, whereas after i.v. administration, the half-lives were <1 hour. Metabolism of the ISIS 2302 after s.c. injection was consistent with exonucleolytic cleavage, as previously observed after i.v. administration. In summary, s.c. administration of PS-ODN resulted in prolonged and extensive absorption of the ODN.     

Interindividual variability in the enantiomeric disposition of ibuprofen following the oral administration of the racemic drug to healthy volunteers

The plasma disposition of the enantiomers of ibuprofen has been investigated following the oral administration of the racemic drug (400 mg) to 24 healthy male volunteers. The plasma elimination of (R)-ibuprofen was found to be more rapid than that of the S-enantiomer [plasma half-life: (R) 2.03 h; (S) 3.05 h; 2P less than 0.001], resulting in a progressive enrichment in the plasma content of this isomer, some 64% of the total area under the plasma concentration time curves (AUC) being due to the pharmacologically active enantiomer. The influence of dose on the pharmacokinetic characteristics of the enantiomers of ibuprofen, over the range 200-800 mg, was investigated in three subjects. Examination of dose-normalized AUC values and oral clearance indicate the dose dependence of (R)-ibuprofen disposition.     

A HPLC method for determination of nicousamide in dog plasma and its application to pharmacokinetic studies

A sensitive and reproducible high performance liquid chromatography (HPLC)-UV method for determination of nicousamide, an inhibitor of rennin and transforming growth factor-beta1 (TGF-beta1) type II receptors, has been developed and validated. Following acetonitrile deproteiniation, samples were separated by isocratic reversed-phase HPLC on an Aichrom Bond-AQ C(18) column and quantified using UV detection at 320 nm. The mobile phase was acetonitrile/water (ratio 62:38 containing 0.1% H(3)PO(4)), with a flow-rate of 1.0 ml/min. A linear curve over the concentration range 5-200 ng/ml (r(2)=0.9978) was obtained. The coefficients of the variation for the intra- and inter-day precisions ranged from 1.4-10.7% and 1.8-7.1%, respectively. The percentage of relative recovery was 91.56-105.45%. The method was used to determine the plasma concentration-time profiles for nicousamide after oral doses of 30, 100 and 300 mg/kg in dogs. A nonlinear pharmacokinetics was found in dogs at doses from 30 to 300 mg/kg. Following 30 mg/kg oral dose, the C(max) and AUC in females were lower than that in male. There is a potential for accumulation in dogs following multiple doses.