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1.
J Pharm Pharmacol ; 58(1): 27-35, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16393461

ABSTRACT

The pharmacokinetics (including distribution in the gastrointestinal tract) of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034) has been investigated in several mouse and rat models of chemically-induced inflammatory bowel disease (IBD). In the female ICR mouse model, IBD was induced by dextran sulfate and the mice administered 30 mg kg(-1) DA-6034 intravenously or orally. In the male SJL mouse model of IBD induced by oxazolone, 30 mg kg(-1) DA-6034 was administered orally. In the male Sprague-Dawley rat model of IBD induced by trinitrobenzene sulfonic acid (TNBS), 10 mg kg(-1) DA-6034 was administered intravenously and orally. After intravenous administration, the total area under the plasma concentration-time curve from time zero to the last measured time, t, in plasma (AUC(0-t)) values were comparable between control and dextran sulfate-induced IBD mice, and between control and TNBS-induced rats. This suggested that the disposition of DA-6034 was not affected considerably by dextran sulfate in mice and TNBS in rats. However, after oral administration in mice and rats with IBD, the AUC(0-t) values were greater compared with the respective controls. This could have been due to an increase (slow) in the gastrointestinal transit time (in IBD mice and rats, the percentages of the oral dose recovered from the rinsing fluid of the small intestine and large intestine as unchanged drug were greater and smaller, respectively), and an increase in intestinal permeability.


Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Flavonoids/pharmacokinetics , Inflammatory Bowel Diseases/metabolism , Administration, Oral , Animals , Anti-Inflammatory Agents/blood , Dextran Sulfate/pharmacology , Female , Flavonoids/blood , Inflammatory Bowel Diseases/chemically induced , Injections, Intravenous , Intestine, Small/drug effects , Intestine, Small/pathology , Male , Mice , Mice, Inbred ICR , Oxazolone/pharmacology , Rats , Rats, Sprague-Dawley , Trinitrobenzenesulfonic Acid/pharmacology
2.
Eur J Pharm Sci ; 27(4): 363-74, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16387482

ABSTRACT

The pharmacokinetics of DA-6034 in rats and dogs and first-pass effect in rats were examined. After intravenous administration, the dose-normalized AUC(0-infinity) values at 25 and 50mg/kg were significantly smaller than that at 10mg/kg. This could be due to significantly slower Cl(r) values than that at 10mg/kg, possibly due to saturated renal secretion at doses of 25 and 50mg/kg. After oral administration, the dose-normalized AUC(0-12h) values at 50 and 100mg/kg were significantly smaller than that at 25mg/kg, possibly due to poor water solubility of the drug. The low F-value (approximately 0.136%) of DA-6034 at a dose of 50mg/kg in rats could be due to considerable intestinal first-pass effect (approximately 69% of oral dose) and unabsorbed fraction from the gastrointestinal tract (approximately 30.5%). The effect of cola beverage, cimetidine, or omeprazole on the AUC(0-24h) of DA-6034 was almost negligible in rats. Pharmacokinetic parameters of DA-6034 after intravenous and oral administration at various doses were dose-independent in dogs. DA-6034 was not accumulated in rats and dogs after consecutive 7 and 28 days oral administration, respectively. The stability, blood partition, and protein binding of DA-6034 were also discussed.


Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Flavonoids/pharmacokinetics , Intestinal Absorption , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Biological Availability , Dogs , Drug Stability , Erythrocytes/metabolism , Flavonoids/administration & dosage , Flavonoids/therapeutic use , In Vitro Techniques , Inflammatory Bowel Diseases/drug therapy , Injections, Intravenous , Intestine, Large/metabolism , Male , Muscles/metabolism , Rats , Rats, Sprague-Dawley
3.
Biopharm Drug Dispos ; 27(3): 141-5, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16400620

ABSTRACT

It was reported that gastric motility was delayed and gastric acid secretion was reduced in vagotomized dogs which mimics a low gastric acidity in humans. A delay in gastric motility causes long residence of amlodipine in the stomach. More unionized fractions of amlodipine could exist in less acidic conditions of gastrointestinal fluids, since amlodipine is a weak basic drug with pKa of 8.7. Hence, gastrointestinal absorption of amlodipine is expected to be enhanced and the time to reach a peak plasma concentration of amlodipine (Tmax) is faster in vagotomized dogs. This was proven after oral administration of an amlodipine orotate tablet at a dose of 5 mg as amlodipine in vagotomized dogs. For example, in vagotomized dogs, the total area under the plasma concentration-time curve from time zero to the last measured time, 48 h, in plasma (AUC(0-48 h)) was significantly greater (725 versus 348 ng h/ml) and Tmax was significantly shorter (1.50 versus 5.00 h) than those in dogs without vagotomy.


Subject(s)
Amlodipine/pharmacokinetics , Vagotomy , Administration, Oral , Amlodipine/administration & dosage , Amlodipine/blood , Animals , Area Under Curve , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/blood , Calcium Channel Blockers/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Dogs , Gastrointestinal Motility/drug effects , Hydrogen-Ion Concentration , Intestinal Absorption , Male , Mass Spectrometry/methods , Metabolic Clearance Rate , Models, Animal , Solubility , Tablets , Time Factors
4.
Biopharm Drug Dispos ; 27(3): 147-56, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16408258

ABSTRACT

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg in control rats and in rats with water deprivation for 72 h (rat model of dehydration). After intravenous administration in the rat model of dehydration, the Cl(nr) (0.654 versus 0.992 ml/min/kg) and Cl(r) (0.0273 versus 0.0784 ml/min/kg) values were significantly slower than in the controls. The slower Cl(nr) could be due mainly to a significantly smaller total amount of unchanged DA-7867 recovered from the gastrointestinal tract at 24 h (GI(24 h): 5.16% versus 9.21% of intravenous dose) due to impaired liver function in the rat model of dehydration. The slower Cl(r) could be due mainly to a significantly smaller 24 h urinary excretion of unchanged drug (Ae(0-24 h): 4.41% versus 7.75% of intravenous dose) due to urine flow rate-dependent Cl(r) of DA-7867 in the rat model of dehydration. Hence, the Cl was significantly slower in the rat model of dehydration (0.677 versus 1.07 ml/min/kg). After intravenous administration in the rat model of dehydration, the V(ss) of DA-7867 was significantly smaller than in the controls (396 versus 506 ml/kg) due mainly to significantly smaller free (unbound to plasma proteins) fractions of DA-7867 in plasma (6.90% versus 29.2%) in the rat model of dehydration. After oral administration in the rat model of dehydration, the AUC was significantly greater than that in controls (10800 versus 7060 microg min/ml) due mainly to a significantly smaller Ae(0-24 h) than in controls (3.50% and 6.17% of oral dose).


Subject(s)
Oxazolidinones/pharmacokinetics , Water Deprivation/physiology , Administration, Oral , Animals , Area Under Curve , Blood Proteins/metabolism , Blood Urea Nitrogen , Dehydration/physiopathology , Disease Models, Animal , Eating/drug effects , Injections, Intravenous , Liver/drug effects , Liver/pathology , Male , Metabolic Clearance Rate , Organ Size/drug effects , Oxazolidinones/administration & dosage , Oxazolidinones/blood , Rats , Rats, Sprague-Dawley , Time Factors , Tissue Distribution , Urination/drug effects , Weight Loss/drug effects
5.
Biopharm Drug Dispos ; 27(3): 125-31, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16400709

ABSTRACT

A pharmacokinetic interaction between oral DA-8159 and amlodipine was evaluated in male Sprague-Dawley rats. In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC(0-6 h) of amlodipine was significantly greater than the controls (34.5+/-6.01 compared with 28.0+/-4.70 microg min/ml), indicating that amlodipine is metabolized via CYP3A1/2 in rats. It was reported that the metabolism of DA-8159 and the formation of DA-8164 (a metabolite of DA-8159) were mainly mediated via CYP3A1/2 in rats, and amlodipine significantly inhibited the CYP3A2 in rats. Therefore, a pharmacokinetic interaction between the two drugs could be expected. However, after oral administration of DA-8159 at a dose of 30 mg/kg with or without oral amlodipine at a dose of 5 mg/kg to rats, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between the two groups of rats. Similar results were also obtained from amlodipine between with and without DA-8159. The above data indicated that the pharmacokinetic interaction between oral DA-8159 and amlodipine was almost negligible in rats.


Subject(s)
Amlodipine/pharmacokinetics , Penile Erection/drug effects , Pyrimidines/pharmacokinetics , Administration, Oral , Amlodipine/administration & dosage , Amlodipine/blood , Animals , Area Under Curve , Aryl Hydrocarbon Hydroxylases/metabolism , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP3A , Drug Interactions , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Feces/chemistry , Gastrointestinal Tract/metabolism , Injections, Intraperitoneal , Injections, Intravenous , Male , Penile Erection/physiology , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/blood , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/metabolism , Rats , Rats, Sprague-Dawley , Sulfonamides , Time Factors , Troleandomycin/administration & dosage , Troleandomycin/pharmacokinetics , Tyrosine/administration & dosage , Tyrosine/analogs & derivatives , Tyrosine/pharmacokinetics
6.
Biopharm Drug Dispos ; 27(1): 47-51, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16302288

ABSTRACT

Gender differences in the pharmacokinetics of DA-6034 were evaluated after intravenous and oral administration at a dose of 50 mg/kg to male and female Sprague-Dawley rats. After intravenous administration to male rats, although the total area under the plasma concentration-time curve from time zero to time infinity of DA-6034 was not significantly different between male and female rats, the plasma concentrations of DA-6034 were lower from 30 min to 480 min, the mean residence time was significantly shorter (6.28 versus 12.2 min), the percentage of intravenous dose of DA-6034 excreted in 24 h urine as unchanged drug was significantly greater (14.4% versus 10.5% of intravenous dose). After oral administration, the pharmacokinetic parameters of DA-6034 were not significantly different between male and female rats.


Subject(s)
Flavonoids/pharmacokinetics , Administration, Oral , Animals , Female , Flavonoids/administration & dosage , Injections, Intravenous , Male , Rats , Rats, Sprague-Dawley , Sex Factors
7.
Biopharm Drug Dispos ; 27(1): 29-37, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16302289

ABSTRACT

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). After intravenous administration in rats with U-ARF, the time-averaged total body clearance (Cl) was significantly faster (2.45 versus 0.932 ml/min/kg) than controls due to significantly faster nonrenal clearance (2.25 versus 0.855 ml/min/kg) in rats with U-ARF. The faster nonrenal clearance could be 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 (30.3% versus 9.38% of intravenous dose) in rats with U-ARF. In rats with U-ARF, the Vss was significantly larger (1420 ml/kg compared with 580 ml/kg), but this was not due to a difference in plasma protein binding; the values were comparable between the two groups of rats. After oral administration to rats with U-ARF, the total area under the plasma concentration-time from time zero to time infinity (AUC) of DA-7867 was significantly smaller than the controls (2560 microg min/ml versus 7440 microg min/ml), and this was not due mainly to a decrease in absorption from the gastrointestinal tract in rats with U-ARF.


Subject(s)
Acute Kidney Injury/metabolism , Anti-Infective Agents/pharmacokinetics , Oxazolidinones/pharmacokinetics , Acute Kidney Injury/chemically induced , Administration, Oral , Animals , Anti-Infective Agents/administration & dosage , Injections, Intravenous , Male , Oxazolidinones/administration & dosage , Rats , Rats, Sprague-Dawley , Tissue Distribution , Uranyl Nitrate
8.
Biopharm Drug Dispos ; 26(9): 411-6, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16163666

ABSTRACT

The changes in pharmacokinetics of DA-8159 by omeprazole with respect to inhibition of CYP3A1/2 in rats were evaluated. After oral administration of DA-8159 at dose of 30 mg/kg to rats pretreated with oral omeprazole at 30 mg/kg for 1 week, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 was significantly greater (37.5% increase) than that in control rats. This could be due to inhibition of metabolism of DA-8159 by inhibition of CYP3A1/2 by omeprazole. The AUC(DA-8164 (a metabolite of DA-8159))/AUC(DA-8159) ratio was also smaller (32.4% decrease) with omeprazole. After oral administration of DA-8159 at a dose of 30 mg/kg to rats without or with cola beverage, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between two groups of rats. This suggested that cola beverage did not have any considerable effects on CYP3A1/2 in rats.


Subject(s)
Beverages , Cola , Enzyme Inhibitors/pharmacology , Omeprazole/pharmacology , Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Cytochrome P-450 CYP3A , Drug Interactions , Male , Membrane Proteins/antagonists & inhibitors , Metabolic Clearance Rate , Penile Erection/drug effects , Rats , Rats, Sprague-Dawley , Sulfonamides
9.
Biopharm Drug Dispos ; 26(7): 309-20, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16035131

ABSTRACT

The pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to spontaneously hypertensive rats (SHRs) at 16 and 6 weeks old and their respective age-matched control normotensive Kyoto-Wistar rats (KW rats), and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats) at 16 weeks old and their age-matched control Sprague-Dawley rats. After oral administration of DA-8159 to 16-week-old SHRs, the AUC values of both DA-8159 (157 versus 103 microg min/ml) and DA-8164 (215 versus 141 microg min/ml) were significantly greater, but the values of DA-8159 were reversed in 16-week-old DOCA-salt rats (125 versus 200 microg min/ml). However, the AUC values of both DA-8159 and DA-8164 were not significantly different between the 6-week-old SHRs and their control rats. The above AUC differences in 16-week-old SHRs may be due to neither hereditary characteristics of SHRs nor the hypertensive state itself.


Subject(s)
Hypertension/metabolism , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Chromatography, High Pressure Liquid , Desoxycorticosterone , Half-Life , Hypertension/chemically induced , Hypertension/genetics , Injections, Intravenous , Kidney/metabolism , Liver/metabolism , Phosphodiesterase Inhibitors/administration & dosage , Piperazines/pharmacokinetics , Purines , Pyrimidines/administration & dosage , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Sildenafil Citrate , Sodium Chloride , Sulfonamides , Sulfones
10.
Biopharm Drug Dispos ; 26(7): 269-77, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15991256

ABSTRACT

Time-averaged total body clearance (Cl) and apparent volume of distribution at steady state (V(SS)) of DA-8159 after intravenous administration to mice (30 mg/kg), rats (30 mg/kg), rabbits (30 mg/kg) and dogs (3 mg/kg) were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict those in humans. Significant linear relationships were obtained between log Cl (l/h) and log W (kg) (r = 0.992; p = 0.0079) and log V(SS) (l) and log W (kg) (r = 0.999; p < 0.0001). The corresponding allometric equations were Cl = 4.36 W(0.492) and V(SS) = 6.41 W(0.911). These allometric equations were extrapolated to predict the Cl and V(SS) for DA-8159 in humans based on the 70 kg body weights. In addition, concentrations in the plasma-time profile predicted using the four animal data fitted to a complex Dedrick plot of animal data. Our results indicated that the DA-8159 data obtained from four laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.


Subject(s)
Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Body Weight , Chromatography, High Pressure Liquid , Dogs , Half-Life , Humans , Injections, Intravenous , Male , Mice , Mice, Inbred ICR , Pyrimidines/administration & dosage , Rabbits , Rats , Species Specificity , Sulfonamides
11.
Biopharm Drug Dispos ; 26(6): 233-41, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15926192

ABSTRACT

In order to find what types of hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of DA-8159 and in the formation of DA-8164 in rats, enzyme inducers, such as dexamethasone, phenobarbital, 3-methylcholanthrene and isoniazid, and enzyme inhibitors, such as troleandomycin and quinine, were pretreated in rats. After a 1 min intravenous administration of DA-8159 at a dose of 30 mg/kg to rats pretreated with dexamethasone (a main inducer of CYP3A1/2 in rats), the total areas under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8159 (283 versus 349 microg min/ml) and DA-8164 (98.0 versus 79.8 microg min/ml) were significantly smaller and greater, respectively, than those in control rats. However, the AUC values of DA-8159 were not significantly different after pretreatment with phenobarbital, isoniazid and 3-methylcholanthrene (main inducers of CYP2B1/2, 2E1 and 1A1/2, respectively, in rats). In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC values of DA-8159 (435 versus 370 microg min/ml) and DA-8164 (34.8 versus 76.5 microg min/ml) were significantly greater and smaller, respectively. However, in rats pretreated with quinine (a main inhibitor of CYP2D1 in rats), the AUC of DA-8159 was comparable to that in control rats. The above data indicate that DA-8159 was metabolized and DA-8164 was formed mainly via CYP3A1/2 in rats.


Subject(s)
Aryl Hydrocarbon Hydroxylases/physiology , Enzyme Inhibitors/pharmacology , Membrane Proteins/physiology , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrimidines/pharmacokinetics , Alcohol Oxidoreductases/physiology , Animals , Area Under Curve , Cytochrome P-450 CYP3A , Cytochrome P450 Family 2 , Enzyme Induction , Injections, Intravenous , Male , Pyrimidines/administration & dosage , Rats , Rats, Sprague-Dawley , Sulfonamides
12.
J Pharm Sci ; 94(7): 1484-93, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15920769

ABSTRACT

Effects of cysteine on the pharmacokinetics of oltipraz were investigated after iv (10 mg/kg) and oral (30 mg/kg) administration to male control, protein-calorie malnutrition (PCM), and PCM with oral cysteine supplementation (PCMC) rats. It was reported that oltipraz was mainly metabolized via hepatic CYP1A1/2, 2B1/2, 2C11, 3A1/2, and 2D1 in male rats. The expression and mRNA levels of CYP1A2, 2C11, and 3A1/2 were also reported to decrease in male PCM rats compared with controls. Interestingly, the decreased CYP isozymes in PCM rats returned fully or partially to controls by oral cysteine supplementation (PCMC rats). Hence, it would be expected that in PCM rats, some pharmacokinetic parameters of oltipraz are fully or partially returned to controls by cysteine. This was proven by the following parameters in PCMC rats: the AUC (328, 782, and 416 mug min/mL for control, PCM, and PCMC rats, respectively, after iv administration, and 223, 456, and 242 mug min/mL after oral administration), terminal half-life (130, 212, and 143 min), mean residence time (MRT) (149, 299, and 189 min), and in vitro CL(int) (0.181, 0.107, and 0.153 mL/min/mg protein) were fully returned to controls, and CL and CL(NR) values were partially returned to controls.


Subject(s)
Cysteine/pharmacology , Protein-Energy Malnutrition/metabolism , Pyrazines/pharmacokinetics , Schistosomicides/pharmacokinetics , Animals , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Injections, Intravenous , Male , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Thiones , Thiophenes
13.
Eur J Pharm Sci ; 25(2-3): 337-45, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15911231

ABSTRACT

Effects of diabetes mellitus induced by streptozotocin (DMIS) on the pharmacokinetics of DA-7867 were investigated after i.v. and oral administration (10mg/kg) to control Sprague-Dawley rats and DMIS rats (at 7th and 29th days after administration of streptozotocin, 45mg/kg). After i.v. administration to DMIS rats, the AUC(0-infinity) values were significantly smaller (50.7 and 64.8% decrease for 7th and 29th days, respectively); this could be due to significantly faster Cl values in the rats (127 and 183% increase for 7th and 29th days, respectively). The faster Cl values were mainly due to significantly greater amount of unchanged drug excreted in 24-h urine (Ae(0-24h)). The greater Ae(0-24h) in DMIS rats could be due to urine flow rate-dependent renal clearance of DA-7867. After oral administration to DMIS rats, the AUC(0-infinity) values were also significantly smaller (61.3 and 72.6% decrease for 7th and 29th days, respectively); this could also be mainly due to significantly greater Ae(0-24h) in the rats. Streptozotocin-induced hepatotoxicity did not influence considerably on the pharmacokinetics of DA-7867 at 7th day when compared with those at 29th day.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Oxazolidinones/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Injections, Intravenous , Male , Metabolic Clearance Rate , Oxazolidinones/administration & dosage , Rats , Rats, Sprague-Dawley , Streptozocin , Time Factors
14.
Int J Pharm ; 296(1-2): 94-102, 2005 May 30.
Article in English | MEDLINE | ID: mdl-15885460

ABSTRACT

Little is known about chronopharmacokinetics of PDE V inhibitors in rats as well as in humans. Hence, the pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, were investigated after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg administered at 10:00 h versus 22:00 h in rats. After intravenous administration of DA-8159 at 22:00 h, the AUC of DA-8159 was significantly greater (528 versus 368 microg min/ml) due to significantly slower CL (56.1 versus 79.5 ml/min/kg) in the rats. After intravenous administration of DA-8159 at 22:00 h, the AUC of DA-8164 was also significantly greater (108 versus 66.8 microg min/ml) possibly due to significantly greater exposure of the parent drug (AUC of DA-8159). After intravenous administration of DA-8164 at 22:00 h, the CL of DA-8164 was significantly slower; hence, this factor could also contribute to the greater AUC of DA-8164 after intravenous administration of DA-8159. However, after oral administration of DA-8159, the AUC values of both DA-8159 and DA-8164 were not significantly different between 10:00 h and 22:00 h. This was not due to decrease in gastrointestinal absorption of DA-8159 at 22:00 h and may be due to changes in intestinal first-pass effect at 22:00 h. The above data suggested that modification of dosage regimen of oral DA-8159 is not necessary in humans between 10:00 h and 22:00 h. Further studies are needed in humans.


Subject(s)
Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Drug Administration Schedule , Male , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/blood , Phosphodiesterase Inhibitors/pharmacokinetics , Protein Binding/drug effects , Protein Binding/physiology , Pyrimidines/blood , Rats , Rats, Sprague-Dawley , Sulfonamides
15.
Biopharm Drug Dispos ; 26(4): 161-6, 2005 May.
Article in English | MEDLINE | ID: mdl-15803515

ABSTRACT

Species differences in the formation of DA-8164 after intravenous and/or oral administration of DA-8159 to mice, rats, rabbits, dogs and humans were investigated. After intravenous administration of DA-8159, the formation of DA-8164 decreased in the order mice, rats, rabbits and dogs; the AUC(DA-8164)/AUC(DA-8159) ratios were 0.479, 0.199, 0.0452 and close to 0 (DA-8164 was below the detection limit in dog plasma), respectively. After oral administration of DA-8159, the formation of DA-8164 was considerable in mice, rats and humans, but almost negligible in dogs; the AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios were 2.99, 2.67, 1.39 and 0.0650, respectively. The above data suggested that the formation of DA-8164 was almost negligible after both intravenous and oral administration in dogs. The species differences for the formation of DA-8164 may be due to the involvement of different CYP isozymes for each species and/or a different amount or activity of CYP isozyme if the same CYP isozyme is involved for the formation of DA-8164 for all species. The AUC (or AUC(0-t))(DA-8164)/AUC (or AUC(0-t))(DA-8159) ratios after oral administration were greater than those after intravenous administration in mice, rats and dogs, and this could be due to considerable first-pass (gastric, intestinal and/or hepatic) effects in the species as proved in rats.


Subject(s)
Penile Erection/drug effects , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Biological Availability , Chromatography, High Pressure Liquid , Dogs , Humans , Infusions, Intravenous , Male , Mice , Mice, Inbred ICR , Pyrimidines/administration & dosage , Pyrimidines/blood , Rabbits , Rats , Rats, Sprague-Dawley , Species Specificity , Sulfonamides
16.
Biopharm Drug Dispos ; 26(5): 173-82, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15841492

ABSTRACT

After intravenous (at doses of 1, 2, 5, and 10 mg/kg) and oral (at doses of 1, 5, and 10 mg/kg) administration of torasemide, the pharmacokinetic parameters were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses; the values were 95.6, 98.8, and 97.3% for oral doses of 1, 5, and 10 mg/kg, respectively. The high F values indicated that the first-pass (gastric, intestinal, and hepatic) effects of torasemide in rats could be almost negligible. After intravenous administration, the total body clearances of torasemide were extensively slower than the reported cardiac output in rats and hepatic extraction ratio was only 3-4% suggesting almost negligible first-pass effects of torasemide in the heart, lung, and liver in rats. Based on in vitro rat tissue homogenate studies, the tissues studied also showed negligible metabolic activities for torasemide. Equilibrium of torasemide between plasma and blood cells of rat blood reached fast and plasma-to-blood cells concentration ratio was independent of initial blood concentrations of torasemide, 1, 5, and 10 microg/ml; the mean value was 0.279. Protein binding of torasemide to fresh rat plasma was 93.9 +/- 1.53% using an equilibrium dialysis technique.


Subject(s)
Diuretics/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Biological Availability , Diuretics/administration & dosage , Diuretics/blood , Drug Stability , Half-Life , Injections, Intravenous , Liver/metabolism , Male , Metabolic Clearance Rate , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Sulfonamides/blood , Tissue Distribution , Torsemide
17.
Res Commun Mol Pathol Pharmacol ; 117-118: 179-87, 2005.
Article in English | MEDLINE | ID: mdl-18426088

ABSTRACT

Pharmacokinetic parameters of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to control rats and rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). After intravenous and oral administration of DA-8159, most of the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between two groups of rats. This suggested that the pharmacokinetic parameters of DA-8159 and DA-8164 were not affected considerably by KPLPS.


Subject(s)
Lipopolysaccharides/pharmacology , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Area Under Curve , Chromatography, High Pressure Liquid , Erectile Dysfunction/drug therapy , Half-Life , Infusions, Intravenous , Injections, Intravenous , Klebsiella pneumoniae/chemistry , Male , Phosphodiesterase Inhibitors/pharmacology , Piperazines/pharmacology , Purines/pharmacology , Pyrimidines/blood , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Sildenafil Citrate , Sulfonamides , Sulfones/pharmacology , Vasodilator Agents/pharmacology
18.
Biopharm Drug Dispos ; 26(2): 67-75, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15617136

ABSTRACT

Almost negligible hepatic metabolism (minor role of liver for the metabolism) and extensive urinary and fecal excretion of DA-7867 were investigated after intravenous administration at a dose of 10 mg/kg to rats. Pharmacokinetic parameters, especially nonrenal clearances of DA-7867, were very similar between control rats and rats pretreated with SKF 525-A, a nonspecific inhibitor of CYP isozymes, in rats. Similar results were also obtained between control rats and rats with liver cirrhosis induced by dimethylnitrosamine. Hepatic first-pass effect of DA-7867 was almost negligible in rats; the areas under the plasma concentration-time curve from time zero to time infinity of DA-7867 were not significantly different between intravenous and intraportal administration. The above data indicated that liver had almost negligible metabolic activity for DA-7867 in rats. Since metabolism of DA-7867 was not considerable in rats, urinary and fecal excretion of the drug was measured for up to 14 days in ten rats. Fecal excretion was the major route for elimination of DA-7867 in rats; approximately 85.0% of intravenous dose of DA-7867 at 10 mg/kg was recovered from urine (17.0% of intravenous dose), feces (64.0% of intravenous dose), washings of the metabolic cage (3.16% of intravenous dose), and entire gastrointestinal tract (0.421% of intravenous dose).


Subject(s)
Anti-Infective Agents/pharmacokinetics , Feces/chemistry , Oxazolidinones/pharmacokinetics , Animals , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/metabolism , Area Under Curve , Dimethylnitrosamine/toxicity , Enzyme Inhibitors/pharmacology , Injections, Intravenous , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/physiopathology , Male , Metabolic Clearance Rate/drug effects , Oxazolidinones/blood , Oxazolidinones/urine , Proadifen/pharmacology , Rats , Rats, Sprague-Dawley , Tail/blood supply , Time Factors , Tissue Distribution
19.
J Pharm Pharmacol ; 56(12): 1543-50, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15563761

ABSTRACT

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.


Subject(s)
Erectile Dysfunction/drug therapy , Protein-Energy Malnutrition/drug therapy , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Administration, Oral , Animals , Erectile Dysfunction/blood , Infusions, Intravenous , Male , Protein-Energy Malnutrition/blood , Pyrimidines/blood , Rats , Rats, Sprague-Dawley , Sulfonamides
20.
Biopharm Drug Dispos ; 25(6): 273-82, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15334627

ABSTRACT

In rats pretreated with dexamethasone (an inducer of CYP3A1/2 in rats) and troleandomycin (an inhibitor of CYP3A1/2 in rats), the area under the plasma concentration-time curve from time zero to time infinity (AUC) values of clarithromycin were significantly smaller (365 compared with 600 micro g min/ml) and greater (1410 compared with 581 micro g min/ml), respectively, than those in control rats. This indicated that clarithromycin was metabolized via CYP3A1/2 in rats. The expression of CYP3A1(23) increased in rats with acute renal failure induced by uranyl nitrate (rats with U-ARF). Hence, it could be expected that AUC of clarithromycin could be smaller in rats with U-ARF. However, after intravenous administration of clarithromycin at a dose of 20mg/kg, the AUC and time-averaged total body (Cl) and nonrenal (Cl(nr)) clearance values were comparable between the two groups of rats. The 9000 x g supernatant fraction of liver homogenates in rats with U-ARF had comparable metabolic activities for clarithromycin compared with those in control rats, suggesting that the CYP3A isozyme responsible for metabolism of clarithromycin seemed not to be expressed considerably in the rats. This could explain the comparable AUC, Cl and Cl(nr) values of clarithromycin between the two groups of rats.


Subject(s)
Acute Kidney Injury/metabolism , Anti-Bacterial Agents/pharmacokinetics , Clarithromycin/pharmacokinetics , Acute Kidney Injury/chemically induced , Animals , Area Under Curve , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases/biosynthesis , Cytochrome P-450 CYP3A , Dexamethasone/pharmacology , Enzyme Induction/drug effects , Half-Life , Injections, Intravenous , Isoenzymes/metabolism , Male , Membrane Proteins/agonists , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/biosynthesis , Rats , Rats, Sprague-Dawley , Time Factors , Troleandomycin/pharmacology , Uranyl Nitrate
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