Gastrointestinal absorption of a new reversible proton pump inhibitor, YJA-20379-8, and its pharmacokinetics after oral administration in acetic acid-induced gastric ulcer in rats.

The absorption of YJA-20379-8 (3-butyryl-4-[5-(R)-(+)-methylbenzylamino]-8-ethoxy-1,7-naphthyrid ine) from various rat gastrointestinal segments was evaluated using in-situ closed-loops. The pharmacokinetics of the drug were also evaluated after oral administration to rats with acetic acid-induced gastric ulcer (AIURs). The concentrations of YJA-20379-8 in the biological samples were analyzed by HPLC. The absorption of YJA-20379-8 from stomach and jejunum was fast, but approximately 50% of the drug was recovered from each segment at 24 h. The total areas under the plasma concentration-time curves from time zero to 24h (AUC(0-24h)) were 161, 392, 233, 365, and 226 microg min mL(-1) for stomach, duodenum, jejunum, ileum, and colon, respectively. After oral administration of the drug, the plasma concentrations and the resultant AUC (0- 12h) were not significantly different between control and AIURs. The detection limits of YJA-20379-8 in human plasma and urine were 50 and 100 ng mL(-1), respectively. The results suggest that modification of the oral dose of YJA-20379-8 may not be required in gastric ulcer patients if the present rat pharmacokinetic data could be extrapolated to man.     

Gastrointestinal first-pass effect of YJA-20379-8, a new reversible proton pump inhibitor, in rats.

Since low bioavailability of YJA-20379-8 (3-butyryl-4-[5-R-(+)-methylbenzylamino]-8ethoxy-1,7-naph thy ridine), a new reversible proton pump inhibitor, has been reported after oral administration of the drug to rats, the first-pass organ of the drug was investigated in rats. YJA-20379-8, 50 mg kg(-1), was infused over 1 min via the jugular vein (n=5) or the portal vein (n=5), or was instilled directly into the stomach (n=5) or the duodenum (n=5). After intravenous or intraportal infusion of the drug, the total body clearance of YJA-20379-8 (18.1 and 19.7 mL min(-1) kg(- 1) based on plasma data) was considerably lower than the reported cardiac output (296 mL min(-1) kg(-1) based on blood data) in rats. This data indicated that the first-pass effect of YJA-20379-8 by the lung and heart was negligible. The areas under the plasma concentration-time curve from time zero to time infinity (AUC) after intravenous or intraportal administration of YJA-20379-8 (2760 and 2540 microg min mL(-1)) were not significantly different, indicating that the hepatic first-pass effect of the drug was also negligible in rats. After intragastric or intraduodenal instillation of YJA-20379-8, the extent of absolute oral bioavailability was 18.2 and 33.8%, respectively. Based on gastrointestinal recovery studies, approximately 86.5 and 91.2% of YJA-20379-8 was absorbed from rat gastrointestinal tract after intragastric or intraduodenal instillation, respectively. The data indicated that gastrointestinal and intestinal first-pass effects of YJA-20379-8 were approximately 68% (86.5-18.2) and 57% (91.2-33.8), respectively. The AUC(0-24h) values of YJA-20379-8 were significantly different between intragastric and intraduodenal instillation, indicating that the gastric first-pass effect of the drug was approximately 10% in rats. Therefore, it could be concluded that the low F value of YJA-20379-8 after oral administration of the drug could be due to a considerable (approx. 60%) intestinal first-pass effect in rats.     

Pharmacokinetics of intravenous and oral DA-8159, a new erectogenic, in rats with protein-calorie malnutrition

Influence of dietary protein deficiency on the pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, was investigated after intravenous and oral administration of DA-8159 at a dose of 30 mg kg(-1) to male Sprague-Dawley rats allowed free access to a 23% (control) or 5% (protein-calorie malnutrition, PCM) casein diet for 4 weeks. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8164 were significantly smaller after both intravenous (87.0 vs 162 microg min mL(-1)) and oral (144 vs 319 microg min mL(-1)) administration of DA-8159 to PCM rats. This could be due to the decrease in CYP3A1/2 (50-60%) in the rats because DA-8164 was mainly formed via CYP3A1/2 in rats. This could be supported by significantly slower in-vitro CL(int) (2.04+/-0.646 vs 3.15+/-0.693 microL min(-1) (mg protein)(-1)) for the formation of DA-8164 in hepatic microsomal fraction of PCM rats. After intravenous administration of DA-8159, the AUC values of DA-8159 were not significantly different between the two groups of rats although the AUC of DA-8164 was significantly smaller in PCM rats, and this may be due to the minor metabolic pathway of DA-8164 in rats. However, after oral administration of DA-8159, the AUC of DA-8159 was significantly greater in PCM rats (194 vs 122 microg min mL(-1)). This was not due to enhanced absorption of DA-8159 from the gastrointestinal tract in the rats but may be due to a decreased intestinal first-pass effect of DA-8159 in the rats.     

Effects of protein-calorie malnutrition on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

The pharmacokinetic parameters of DA-7867, a new oxazolidinone, were compared after intravenous and oral administration at a dose of 10 mg x kg(-1) to control rats and rats with protein-calorie malnutrition (rats with PCM). After intravenous administration of 10 mg x kg(-1) DA-7867 to rats, metabolism of the drug was not considerable and after 14 days approximately 85.0% of the dose was recovered as unchanged drug from urine and faeces. After intravenous administration to rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly smaller (10800 vs 6990 microg min x mL(-1)) compared with control rats. This may have been due to significantly faster total body clearance (CL, 0.930 vs 1.44 mL x min(-1) x kg(-1)). The faster CL in PCM rats could have been due to significantly faster non-renal clearance (0.842 vs 1.39 mL x min(-1) x kg(-1) due to significantly greater gastrointestinal (including biliary) excretion; the amount of unchanged DA-7867 recovered from the entire gastrointestinal tract at 24 h was significantly greater (1.19 vs 4.28% of intravenous dose)) because the renal clearance was significantly slower in PCM rats (0.0874 vs 0.0553 mL x min(-1) x kg(-1)). After oral administration to PCM rats, the AUC was significantly smaller compared with control rats (7900 vs 4310 microg x min x mL(-1)). This could have been due to a decrease in absorption from the gastrointestinal tract.     

Oral bioavailability in pigs of a miconazole/Hydroxypropyl-γ-cyclodextrin/ L-tataric acid inclusion complex produced by supercritical carbon dioxide processing

The objective of this study was to determine the pharmacokinetic parameters of miconazole after oral administration of a miconazole/hydroxypropyl-gamma-cyclodextrin(HPgammaCD)/L-tartaric acid inclusion complex produced by supercritical carbon dioxide processing. The pharmacokinetics of the miconazole ternary complex (CPLX), of the corresponding physical mixture (PHYS), and of miconazole alone (MICO) were compared after oral administration. Six mixed-breed pigs received each formulation as a single dose (10 mg miconazole/kg) in a crossover design. Miconazole plasma concentrations were determined by a high-performance liquid chromatography method. Preliminary in vitro dissolution data showed that CPLX exhibits a faster and higher dissolution rate than either PHYS or MICO. Following CPLX oral administration, mean area under the plasma concentration curve (AUC(0-infinity)) for miconazole was 95.0 +/- 55.8 microg/min/mL, with the peak plasma concentration (C(max) 0.59 +/- 0.39 microg/mL) at 19.30 minutes. The AUC(0-infinity) and C(max) values were significantly higher than those after oral administration of PHYS (AUC(0-infinity) 38.5 +/- 12.7 microg/min/mL and C(max) 0.24 +/- 0.08 microg/mL; P < .1) and of MICO (AUC(0-infinity) 24.1 +/- 14.0 microg/min/mL and C(max) 0.1 +/- 0.05 microg/mL; P < .1). There were also significant differences between PHYS and MICO (P < .1). The results of the study indicate that CPLX shows improved dissolution properties and a higher relative oral bioavailability compared with PHYS and MICO.     

Pharmacokinetic interaction between oltipraz and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) after single intravenous and oral administration to rats

The aim of this study was to report the pharmacokinetic interaction between oltipraz (50 mg kg(-1)) and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB, 10 mg kg(-1)) after single intravenous and oral administration to rats. After intravenous administration of oltipraz plus DDB, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of oltipraz was significantly greater (1440 vs 1740 microg min mL(-1)) than that after oltipraz alone. This was not due to slower clearances of oltipraz after oltipraz plus DDB since the total body, renal and nonrenal clearances were comparable between the two groups of rats. It could be due to a decrease in tissue binding of oltipraz by DDB. The apparent volume of distribution at steady state (Vd(ss)) of DDB was significantly smaller (7060 vs 4650 mL kg(-1)) than after oltipraz alone. After oral administration of oltipraz plus DDB, the AUC of olitpraz was also significantly greater (479 vs 583 microg min mL(-1)) than that after oltipraz alone. This was not due to increased absorption of oltipraz from the rat gastrointestinal tract after oltipraz plus DDB but again could be due to a decrease in Vd(ss) of oltipraz by DDB. However, after both intravenous and oral administration, the pharmacokinetic parameters of DDB were comparable between DDB alone and DDB plus oltipraz, indicating that oltipraz did not greatly affect the pharmacokinetics of DDB in rats.     

Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-alpha in rats

Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-alpha for 8 days (4MIU kg(-1), once daily) or with pegylated-IFN-alpha (ViraferonPeg; 60 microg kg(-1), Days 1, 4 and 7). The rats were then distributed into sub-groups (n = 5-6) according to the pre-treatment type, and received one dose of [(14)C]DTX (20 mgkg(-1)) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-alpha both increased DTX oral bioavailability parameters: C(max) (17.0+/-4.0 microg L(-1) (P < 0.02) and 18+/-5.5 microg L(-1) (P < 0.05), respectively, vs 7.4+/-2.5 microg L(-1) for the control) and AUC (0.036+/-0.010 microg h mL(-1) (P < 0.01) and 0.033+/-0.009 microg h mL(-1) (P < 0.01), respectively, versus 0.012+/-0.004 microg h mL(-1) for the control). IFN-alpha also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-alpha did not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [(14)C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-alpha modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.     

Pharmacokinetics of a new proton pump inhibitor, YJA-20379-8, after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats

The purpose of this study was to investigate the causes for the differences observed in the pharmacokinetics of YJA-20379-8 in 16-week-old spontaneously hypertensive rats (SHRs). To see if the hereditary characteristics of SHRs was the cause, 20 mg/kg of the drug was intravenously infused over 15 min and 50 mg/kg of the drug was orally administered to 6-week-old SHRs and 16-week-old SHRs and their age-matched control Kyoto-Wistar (KW) rats. Also to see if the hypertensive status itself was the cause, the same doses were administered to 16-week-old deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats (DOCA-salt rats) and their age-matched control Sprague-Dawley rats. The areas under the plasma concentration-time curve from time zero to time infinity (for intravenous study) and to the last sampling time in plasma (for oral study) were significantly smaller after both intravenous and oral administration, and the total body clearances of the drug were significantly faster after intravenous administration to 6-week-old SHRs, 16-week-old SHRs, and 16-week-old DOCA-salt rats than those in their respective age-matched control rats. The above pharmacokinetic parameter changes in 16-week-old SHRs were due to both hereditary characteristic of SHRs and the hypertensive status itself.     

Faster clearance of omeprazole in rats with acute renal failure induced by uranyl nitrate: contribution of increased expression of hepatic cytochrome P450 (CYP) 3A1 and intestinal CYP1A and 3A subfamilies

It has been reported that omeprazole is mainly metabolized via hepatic cytochrome P450 (CYP) 1A1/2, CYP2D1 and CYP3A1/2 in male Sprague-Dawley rats, and the expression of hepatic CYP3A1 is increased in male Sprague-Dawley rats with acute renal failure induced by uranyl nitrate (U-ARF rats). Thus, the metabolism of omeprazole would be expected to increase in U-ARF rats. After intravenous administration of omeprazole (20 mgkg(-1)) to U-ARF rats, the area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly reduced (371 vs 494 microg min mL(-1)), possibly due to the significantly faster non-renal clearance (56.6 vs 41.2 mL min(-1) kg(-1)) compared with control rats. This could have been due to increased expression of hepatic CYP3A1 in U-ARF rats. After oral administration of omeprazole (40 mgkg(-1)) to U-ARF rats, the AUC was also significantly reduced (89.3 vs 235 microg min mL(-1)) compared with control rats. The AUC difference after oral administration (62.0% decrease) was greater than that after intravenous administration (24.9% decrease). This may have been primarily due to increased intestinal metabolism of omeprazole caused by increased expression of intestinal CYP1A and 3A subfamilies in U-ARF rats, in addition to increased hepatic metabolism.     

Pharmacokinetics of BOF-4272, a xanthine oxidase inhibitor, after single intravenous or oral administration to male mice and rats.

BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulphinylphenyl) pyrazolo [1,5-a]-1,3,5-triazine-4 (1H)-one), is a new drug intended for the treatment of hyperuricaemia. This report describes the detailed pharmacokinetics of BOF-4272 in mice and rats after intravenous or oral administration. Plasma concentrations of BOF-4272 at 2-8h after intravenous administration were significantly higher in mice than in rats. Plasma concentrations of BOF-4272 after oral administration were significantly higher in fed mice than in fasted mice, but were similar in fasted and fed rats. The elimination half-life of the distribution phase (t1/2(alpha)) was similar in mice (0.158 h) and rats (0.210 h). The elimination half-life of the terminal elimination phase (t1/2(beta)) in mice was 1.936 h, while that in rats was 0.742 h. The volume of the central compartment (V1) was almost the same in mice (415 mL kg(-1)) and rats (440 mL kg(-1)). However, the volume of the peripheral compartment (V2) in mice was 1068 mL kg(-1), while that in rats was 92 mL kg(-1). The steady-state volume of distribution (Vss) was 2.8 times larger in mice than in rats. The area under the plasma concentration-time curve (AUC) in mice was 5332 ng h mL(-1), while that in rats was 3806 ng h mL(-1). The AUC0-24 h after oral administration was 2.5 times greater in fed mice than in fasted mice, and was 1.4 times greater in fasted rats than in fed rats. The correlation coefficients of Cmax and AUC0-24 h in both mice and rats after oral administration were greater than 0.997 in the dose range 1 - 125 mg kg(-1), indicating that the linear range of absorption or elimination (or both) of BOF-4272 is very wide. The results of the present study demonstrate that the mouse is a suitable animal species for evaluating the clinical pharmacokinetics of BOF-4272.     

Gastroprotection and effect of the simultaneous administration of Cuachalalate (Amphipterygium adstringens) on the pharmacokinetics and anti-inflammatory activity of diclofenac in rats

This work aimed to study the effect of Cuachalalate methanol extract (CME) on the anti-inflammatory activity and pharmacokinetics of diclofenac sodium, a frequently prescribed non-steroidal anti-inflammatory drug (NSAID). The gastroprotective effect of CME on the gastric injury induced by diclofenac was studied in rats. CME showed a gastroprotective effect of 15.7% at 1 mg kg(-1) and 72.5% at dose of 300 mg kg(-1). Omeprazole, used as anti-ulcer reference drug, showed gastroprotective effects of 50-89.7% at doses tested (1-30 mg kg(-1)). The value of the 50% effective dose for the anti-inflammatory effect of diclofenac sodium (ED50 = 1.14 +/- 0.23 mg kg(-1)) using carrageenan-induced rat paw oedema model, was not modified by the concomitant administration of 30 or 100 mg kg(-1) of CME. The effect of CME (30, 100 and 300 mg kg(-1), p.o.) on the pharmacokinetics of diclofenac sodium was studied. It was observed that the simultaneous administration of diclofenac sodium and 300 mg kg(-1) of CME decreased significantly the values of Cmax (7.08 +/- 1.42 microg mL(-1)) and AUC (12.67 +/- 2.97 microg h mL(-1)), but not the value of tmax (0.13 (0.1-0.25)h) obtained with the administration of diclofenac alone. The simultaneous administration of 30 or 100 mg kg(-1) of CME did not modify the pharmacokinetic parameters of diclofenac. The experimental findings in rats suggest that CME at doses lower than 100 mg kg(-1) protects the gastric mucosa from the damage induced by diclofenac sodium without altering either the anti-inflammatory activity or the pharmacokinetics of this NSAID.     

Pharmacokinetics and therapeutic effects of oltipraz after consecutive or intermittent oral administration in rats with liver cirrhosis induced by dimethylnitrosamine

Pharmacokinetics and therapeutic effects of oltipraz were evaluated after consecutive (once per day at 30 mg/kg/day for 7 and 14 days) or intermittent (once per week at 100 mg/kg/week for 1-3 weeks) oral administration to rats with liver cirrhosis induced by dimethylnitrosamine. The AUC of oltipraz was significantly greater in cirrhotic rats than controls (890 compared with 270 microg . min/mL) due to impaired liver function in cirrhotic rats. However, the AUC values after consecutive 7 (421 compared with 753 microg . min/mL) and 14 (309 compared with 821 microg . min/mL) days oral administration of oltipraz in cirrhotic rats were significantly smaller than those in respective vehicle-treated cirrhotic rats. Moreover, the AUC values after intermittent 2 and 3 weeks in cirrhotic rats were also significantly smaller than that in 1 week vehicle-treated cirrhotic rats (2370 and 1690 compared with 4760 microg . min/mL). This could be due to induction of CYP isozymes and considerably greater numbers of normal liver cells in cirrhotic rats by oral administration of oltipraz. Improved liver function by oltipraz in cirrhotic rats was proved by liver microscopy; livers are free of significant fibrosis, although evidence of bridging necrosis is still present in many rats.     

ET(B) receptor agonist, IRL 1620, does not affect paclitaxel plasma pharmacokinetics in breast tumour bearing rats

Endothelins are potent endogenous vasoactive substances. We have found that intravenous administration of endothelin (ET)B receptor agonist, IRL 1620 (N-suc-[Glu9, Ala(11,15)]ET-1 (8-21)) to tumour bearing rats increases blood perfusion and enhances delivery of chemotherapeutic agents to the tumour tissue. This study was conducted to determine whether IRL 1620, an ET(B) receptor selective agonist, alters pharmacokinetics of paclitaxel in breast tumour bearing rats. Breast tumours were induced in female Sprague-Dawley rats by N-methyl-n-nitrosourea (50 mg kg(-1), i.p). Saline (0.3 mL kg(-1), i.v.) or IRL 1620 (3 nmol kg(-1), i.v.), was administered to the tumour bearing rats via the tail vein. Paclitaxel (3 mg kg(-1), i.v.) was administered 15 min after saline or IRL 1620 injection. Serial plasma samples were collected up to 10 h after paclitaxel administration and analysed using an HPLC-UV assay. In a similar study [3H]-paclitaxel (40 microCi, i.v.) was administered after saline or IRL 1620 injection as described above and serial plasma samples were collected until 24 h. Data was fitted to a three-compartment model and pharmacokinetic parameters were generated using WinNonlin software. The AUC(0-infinity) (9.42 +/- 3.18 microg h mL(-1)), clearance (0.69 +/- 0.17 L h(-1) kg(-1)), volume of distribution (10.31 +/- 4.54 L kg(-1)) and half life (1.00 +/- 0.32 h) of [3H]-paclitaxel in tumour rats were similar in rats treated with IRL 1620 or vehicle. Tumour concentration of [3H]-paclitaxel was determined in rats treated with IRL 1620 or vehicle and there was a significant increase in tumour paclitaxel concentration (308.59 +/- 24.42%) in rats treated with IRL 1620 compared with vehicle. It is concluded that IRL 1620, an ET(B) receptor agonist, does not alter paclitaxel pharmacokinetics and can selectively augment the delivery of paclitaxel to the tumour tissue.     

Effect of sodium diclofenac on the bioavailability of amoxicillin

The aim of this study was to evaluate the effect of sodium diclofenac on the bioavailability of amoxicillin. In this randomised, crossover study with a 1-week washout period, 20 volunteers received a 2g oral dose of amoxicillin (Amoxil) (Group 1) or a 2g oral dose of amoxicillin with 100 mg of sodium diclofenac (Voltaren) (Group 2). Blood samples were collected at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 4, 6, 8, 12 and 24h following drug administration. High-performance liquid chromatography with ultraviolet detection was used to quantify plasma amoxicillin concentrations. Bioassay (Micrococcus luteus ATCC 9341) was performed to verify the antimicrobial efficacy of amoxicillin in vitro. The pharmacokinetic parameters area under the plasma concentration-time curve (AUC), maximum plasma concentration observed during the 24-h study period (C(max)) and renal clearance (CL) were analysed by analysis of variance, and time at which C(max) occurred (T(max)) and volume of distribution (VD) were analysed by Wilcoxon test (P<0.05). For Group 1, the mean (+/- standard deviation) AUC(0-24), C(max) and T(max) values were 3391.8+/-1186.7 microg min/mL, 17.3+/-6.5 microg /mL and 121.5+/-20.6 min, respectively; and for Group 2, the values were 2918.4+/-1024.8 microg min/mL, 15.5+/-5.8 microg /mL and 136.5+/-30.0 min, respectively. Lower values of AUC and C(max) were observed for Group 2 (P<0.05). CL of amoxicillin increased (P< 0.05) by 18.5% in Group 2, suggesting that sodium diclofenac may interfere with amoxicillin renal excretion. In conclusion, sodium diclofenac can significantly reduce the bioavailability of amoxicillin.     

Extremely low bioavailability of magnesium lithospermate B, an active component from Salvia miltiorrhiza, in rat

We assessed the bioavailability of magnesium lithospermate B (MLB), a main polyphenolic component of Salvia miltiorrhiza and a potent antioxidant having various pharmacological activities, to evaluate its action in vivo. The plasma concentrations of lithospermic acid B (LSB) showed a biexponential decrease after intravenous administration of MLB to rats at doses of 4 and 20 mg/kg. The values of area under the concentration-time curve (AUC; 87.8 +/- 10.9 and 1130 +/- 329 microg.min/mL), total body clearance (CL (tot); 55.52 +/- 7.07 and 23.51 +/- 5.98 mL/min/kg), and distribution volume at steady state (V (ss); 7.60 +/- 1.03 and 3.61 +/- 1.16 L/kg) suggested non-linear pharmacokinetics between the two doses. After oral administration of MLB at a high dose of 100 mg/kg, the mean AUC was barely 1.26 +/- 0.36 microg.min/mL. Absolute bioavailability of MLB was calculated to be 0.0002 from the AUC values after both intravenous dosing at 20 mg/kg and oral dosing at 100 mg/kg. The extremely low bioavailability was caused mainly by poor absorption from the rat gastrointestinal tract; about 65 % of the dose was retained in the tract even 4 h after oral administration, and most of the dose was retained even 20 min after infusion in an in situ jejunal loop experiment. Urinary and biliary excretion of LSB were only 0.70 % +/- 0.26 % and 5.10 % +/- 2.36 %, respectively, over a 30 h time period after intravenous injection despite the large CL (tot) and V (ss) values, and were much less (0.010 % +/- 0.001 % and 0.12 % +/- 0.04 %) after oral dosing. These findings suggest that extensive metabolism, including a first-pass effect, and wide distribution of LSB besides the poor absorption contributed significantly to the extremely low systemic bioavailability.     

Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver

The pharmacokinetics of an intravenous and oral diclofenac dose of 3.2 mg/kg was studied in male Wistar rats under control conditions, 1 and 3 days after liver damage and regeneration induced by an oral injection of CCl(4). One day after CCl(4) administration, indicators of necrosis (alanine aminotransferase), cholestasis (gamma-glutamyl transpeptidase) and regeneration (alpha-fetoprotein) were significantly increased; these effects were reversed after 3 days. In nonintoxicated rats, t(1/2) was 43.83 +/- 4.95 min, V(d) was 0.37 +/- 0.04 l/kg, Cl was 129.21 +/- 9.20 ml/min kg, AUC(i.v.) was 25.62 +/- 1.45 microg/min ml, and AUC(p.o.) was 20.21 +/- 1.03. One day after intoxication, when the liver was damaged and regenerating, the metabolism was decreased: diclofenac t(1/2) was increased to 258.21 +/- 30.80 min but V(d) did not change significantly, therefore Cl was reduced to 32.81 +/- 3.38 ml/min kg. By day 3 after intoxication, liver function, regeneration and pharmacokinetics returned to normal. The results show that liver damage and regeneration increases the bioavailability by decreasing elimination. The present observations suggest that reduction of the pharmacokinetic parameters may lead to drug accumulation in the regenerating-damaged liver with an attendant possible increase in toxic effects. The results in rats, also suggest that once hepatic injury is finished and regeneration is complete, diclofenac can be administered normally.     

Pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidine-7-one (DA-8159) and nitroglycerin in rats

The pharmacokinetic interaction between 5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo (4,3-d)pyrimidine-7-one (DA-8159), a new erectogenic, and nitroglycerin has been evaluated in rats. Male Sprague-Dawley rats received DA-8159 (30 mg kg(-1)) as a single intravenous or oral dose with the simultaneous single intravenous administration of nitroglycerin (2.5 mg kg(-1)). After simultaneous intravenous administration, the total area under the plasma concentration-time curve from time zero to time infinity (AUC(inf)) of DA-8159 (746 vs 457 microg min mL(-1)) was found to be significantly greater than with DA-8159 alone. Also, after simultaneous intravenous administration total body clearance (CL) (40.2 vs 65.6 mL min(-1) kg(-1)), renal clearance (CL(R)) (1.65 vs 5.11 mL min(-1) kg(-1)), and nonrenal clearance (CL(NR)) (38.3 vs 60.2 mL min(-1) kg(-1)) of DA-8159 were significantly slower compared with DA-8159 alone. The slower CL(NR) of DA-8159 could have been due to the inhibition of the metabolism of DA-8159 by nitroglycerin, since DA-8159 is metabolized via CYP3A1/2 in rats and nitroglycerin inhibits CYP3A1/2 in rats. The slower CL(R) of DA-8159 could have been due to the urine flow rate-dependent CL(R) of DA-8159 in rats. After the simultaneous intravenous administration of nitroglycerin and DA-8159, the AUC(inf) of nitroglycerin was significantly smaller (635 vs 960 microg min mL(-1)), which could have been due to the cardiac output-dependent CL of nitroglycerin. However, after the oral administration of DA-8159, the pharmacokinetic parameters of DA-8159 with and without the intravenous administration of nitroglycerin became comparable. This was not due to the decrease in nitroglycerin's gastrointestinal absorption of DA-8159, but could have been due to changes in nitroglycerin's intestinal firstpass effect of DA-8159. Human studies are required to determine the administration time of DA-8159 when nitroglycerin is concomitantly taken.     

Influence of infused catecholamines on the pharmacokinetics of cocaine and benzoylecgonine formation after bolus dose or continuous cocaine administration in the rat.

The purpose of this study was to determine whether a catecholamine infusion administered to simulate a stress state could alter the pharmacokinetics of administered cocaine and effect the formation of benzoylecgonine, its major metabolite, in the rat. In a previous investigation we determined that catecholamine infusion enhanced the toxicity of continuous cocaine infusion by reducing the time before the onset of convulsions and respiratory arrest. We postulated that this enhanced toxicity was an effect of catecholamines on the pharmacokinetics of cocaine. To test this hypothesis we studied plasma cocaine and benzoylecgonine disposition after intravenous bolus administration of cocaine (5 mg kg(-1)) to 19 male Sprague-Dawley rats and to 10 rats which received an initial loading-dose cocaine infusion of 1 mg kg(-1) min(-1) (for 5 min) followed by continuous infusion of 100 microg kg(-1) min(-1). Rats in both studies randomly received either continuous catecholamine infusion comprising adrenaline (7.25 microg mL(-1)), noradrenaline (4.4 microg mL(-1)) and dopamine (8.0 microg mL(-1)) or saline, administered at a similar rate. Bolus dose cocaine administration, simultaneously with catecholamine infusion, resulted in significantly higher Cmax levels for cocaine (3.8 compared with 2.5 microg mL(-1)) and lower distribution half-lives (3.3 compared with 5.9 min) and central compartment volumes of distribution (1.5 compared with 2.1 L kg(-1)) compared with saline infusion. Benzoylecgonine formation was significantly reduced in rats receiving catecholamines whereas the elimination half-lives (26.3 compared with 25.0 min) and systemic clearances (146 compared with 146 mL kg(-1) min(-1)) were not different. Continuous cocaine infusion (after an initial loading infusion) resulted in the doubling of plasma cocaine levels in rats receiving catecholamines compared with the control group. These data indicate that elevated plasma catecholamines have significant effects on cocaine pharmacokinetics. This might serve to explain the enhanced toxicity from concomitant cocaine and catecholamine infusion demonstrated in previous experiments.     

Dose-dependent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage, KR-31378, in rats

The dose-dependent pharmacokinetic parameters of a new neuroprotective agent for ischemia-reperfusion damage, KR-31378, were evaluated after intravenous and oral administration, 10, 20, and 50 mg/kg, to rats. After intravenous administration of 50 mg/kg, the dose-normalized (10 mg/kg) AUC (994 microg min/mL) was significantly greater than that at 10 (569 microg min/ml) and 20 (660 microg min/mL) mg/kg. This could be due to slower clearance (Cl) with increasing dosage (18.5, 14.6, and 10.2 mL/min/kg for 10, 20, and 50 mg/kg, respectively). The slower Cl with increasing dosage could be due to saturable metabolism of KR-31378 in rats and this could be supported by significantly slower Cl(nr) and significantly greater 24-h urinary excretion of the drug at 50 mg/kg than those at 10 and 20 mg/kg. After oral administration of 50 mg/kg, the dose-normalized (10 mg/kg) AUC (1160 microg min/mL) was significantly greater than that at 10 (572 microg min/mL) and 20 (786 microg min/mL) mg/kg. Note that the AUCs were comparable (not significantly different) between intravenous and oral administration at each dosage, indicating that the absorption from gastrointestinal tract was almost complete and the first-pass (gastric, intestinal, and hepatic) effect was not considerable after oral administration to rats.     

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.