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Background and Purpose: Temperature-sensitive transient receptor potential ion channels (thermoTRPs) expressed in primary sensory neurons and skin keratinocytes play a crucial role as peripheral pain detectors. Many natural and synthetic ligands have been found to act on thermoTRPs, but little is known about endogenous compounds that inhibit these TRPs. Here, we asked whether resolvin D1 (RvD1), a naturally occurring anti-inflammatory and pro-resolving lipid molecule is able to affect the TRP channel activation., Experimental Approach: We examined the effect of RvD1 on the six thermoTRPs using Ca(2+) imaging and whole cell electrophysiology experiments using the HEK cell heterologous expression system, cultured sensory neurons and HaCaT keratinocytes. We also checked changes in agonist-specific acute licking/flicking or flinching behaviours and TRP-related mechanical and thermal pain behaviours using Hargreaves, Randall-Selitto and von Frey assay systems with or without inflammation., Key Results: RvD1 inhibited the activities of TRPA1, TRPV3 and TRPV4 at nanomolar and micromolar levels. Consistent attenuations in agonist-specific acute pain behaviours by immediate peripheral administration with RvD1 were also observed. Furthermore, local pretreatment with RvD1 significantly reversed mechanical and thermal hypersensitivity in inflamed tissues., Conclusions and Implications: RvD1 was a novel endogenous inhibitor for several sensory TRPs. The results of our behavioural studies suggest that RvD1 has an analgesic potential via these TRP-related mechanisms.

Background and Purpose: Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with alpha-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic cytochrome P450 3A1/2., Experimental Approach: Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg x kg(-1)) and/or tamsulosin (1 mg x kg(-1)). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (K(i)) and [I]/K(i) ratio of udenafil., Key Results: The total area under the plasma concentration-time curve from time zero to time infinity (AUC)s (or AUC(0-4 h)) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs., Conclusions and Implications: The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.

It was reported that the area under the plasma concentration-time curve from time zero to time infinity (AUC) of parathion was significantly smaller, and the time-averaged total body clearance (Cl) of parathion was significantly faster after intravenous administration of parathion to rats pretreated with dexamethasone than those in control rats. This was supported by significantly faster intrinsic clearance of parathion to form paraoxon in hepatic microsomal fraction of rats pretreated with dexamethasone. The above data suggested that parathion was metabolized to paraoxon by dexamethasone-inducible hepatic cytochrome P450 (CYP) 3A in rats. The purpose of this study is to explain the protective effects of physostigmine against paraoxon toxicity by suppressing CYP3A, and hence, decreasing formation of a toxic metabolite, paraoxon. The pharmacokinetic changes of parathion and paraoxon were investigated after intravenous administration of parathion, 3 mg/kg, to control Sprague-Dawley rats, and the rats pretreated with physostigmine (100 microg/kg, intraperitoneal injection 30 min before parathion administration). After a 1-min intravenous infusion of parathion to rats pretreated with physostigmine, the AUC of parathion (60.4 compared with 73.7 microg min/mL) was significantly greater, Cl of parathion (49.7 compared with 40.7 mL/min/kg) was significantly slower, and amount of paraoxon recovered from liver, mesentery and large intestine at 5 min was smaller than those in control rats. Based on in vitro rat hepatic microsomal studies, physostigmine inhibited significantly the erythromycin N-demethylase activity (1.03 compared with 0.924 nmol/mg protein/min), mainly mediated by hepatic cytochrome P450 3A in rats. The above data suggested that the formation of paraoxon was inhibited in rats pretreated with physostigmine by inhibiting CYP3A., (Copyright 2000 John Wiley & Sons, Ltd.)

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., (Copyright 2000 John Wiley & Sons, Ltd.)

After intravenous administration of AS 2-006A, 20, 50, and 90 mg/kg, to rats, the pharmacokinetic parameters, terminal half-life (69.8-86. 6 min), mean residence time (56.2-75.2 min), apparent volume of distribution at steady state (809-1040 mL/kg), and total body clearance (11.4-11.9 mL/min/kg), were dose-independent. After topical application of 0.5 or 1% AS 2-006A ointment, 300 mg, to abraded rat skin, the absorbed amounts were dose (0.5 and 1%) and time (30, 60, 120, 240, 360 and 480 min)-independent; the value was approximately 20%. The tissue-to-plasma ratios of AS 2-006A were greater than unity in all rat tissues studied, except in the muscle and large intestine. AS 2-006A was stable for up to 24 h incubation in rat plasma, and human plasma and urine; however, it seemed not to be stable in rat urine; the disappearance rate constant was 0.0218/h. AS 2-006A reached equilibrium fast between plasma and blood cells, and the equilibrium plasma/blood cells partition ratios were independent of the initial rabbit blood concentrations of AS 2-006A, 10, 20, and 50 microg/mL; the mean values were in the range of 2.38-2.75 for three rabbit blood. The protein binding of AS 2-006A to rat plasma was high, as the drug was under detection limit in the filtrate at the plasma concentrations of the drug, ranging from 7.21 to 228 microg/mL., (Copyright 2000 John Wiley & Sons, Ltd.)

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5-20 mg kg(-1), to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50-200 mg kg(-1), to rats, the area under the plasma concentration-time curve from time zero to 12 or 24 h (AUC(0-12 h) or AUC(0-24 h)) was proportional to the oral dose of the drug, 50-100 mg kg(-1), however, the AUC(0-24 h) value at 200 mg kg(-1) increased with less proportion to the dose increase (324, 689, and 815 microg x min mL(-1) for 50, 100, and 200 mg kg(-1), respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg(-1), respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg(-1). The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg(-1), was approximately 70% (116 versus 163 microg x min mL(-1)) of that after iv administration of the drug, 5 mg kg(-1), to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5-20 mg kg(-1), to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg(-1), to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5-20 mg kg(-1), to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC(0-10 h) values were not significantly different (96.8 versus 98.2 microg x min mL(-1)) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs.

The pharmacokinetics of DA-125 were compared after intravenous (i.v.) administration of the drug, 10 mg kg-1, to control male Sprague-Dawley rats (n = 9) and uranyl nitrate-induced acute renal failure (U-ARF, n = 12) rats, or male Sprague-Dawley rats fed on a 23% (control, n = 8) or a 5% (protein-calorie malnutrition, PCM, n = 9) protein diet. After i.v. administration of DA-125, almost 'constant' plasma concentrations of M1, M2, and M4 were maintained from 1-2 h to 8-10 h in all rat groups due to the continuous formation of M2 from M1 and M4 from M3. The plasma concentrations of M3 were the lowest among M1-M4 for all rat groups due to the rapid and almost complete conversion of M3 to M4 and other metabolite(s). The AUCt values of M1 (115 against 82.5 micrograms min mL-1), M2 (33.0 against 23.6 micrograms min mL-1), and M4 (26.3 against 15.1 micrograms min mL-1) were significantly higher in the U-ARF rats than in the control rats. The percentages of i.v. dose excreted in 24 h urine as M1 (under the detection limit against 0.316%), M2 (under the detection limit against 5.58%), and M4 (0.0174 against 0.719%)--expressed in terms of DA-125--were significantly lower in the U-ARF rats than in the control rats, and this could be due to the decreased kidney function in the U-ARF rats. However, the percentages of i.v. dose recovered from the GI tract at 24 h as M1 (0.0532% against under the detection limit), M3 (0.0286% against under the detection limit), and M4 (0.702% against 0.305%)--expressed in terms of DA-125--were significantly greater in the U-ARF rats than in the control rats. All U-ARF rats had ascites, but the concentrations of M1 (0.0320 micrograms mL-1), M2 (0.0265 micrograms mL-1), M3 (under the detection limit), and M4 (0.032 micrograms mL-1) in the ascites from one rat were almost negligible. The plasma concentrations and most of the pharmacokinetic parameters of M1, M2, and M4 were not significantly different between the PCM rats and their control rats.

Pharmacokinetic parameters of isoniazid obtained from 37 normal subjects were compared with parameters obtained from 14 patients with chronic renal failure. In the 29 normal rapid acetylators and eight normal slow acetylators, the mean plasma half-life values of isoniazid were 1.54 +/- 0.31 and 3.68 +/- 0.59 hours, respectively. The plasma half-life values of isoniazid in patients with chronic renal failure varied widely from 1.30 to 10.13 hours, but the values were significantly longer than those of normal subjects. Because isoniazid clearance is governed mainly by hepatic metabolism, such a significant prolongation of plasma half-life of isoniazid was unexpected; thus the pharmacokinetics of isoniazid were reevaluated in the same patients with chronic renal failure after the kidney transplantation. After successful kidney transplantation, the shortening of isoniazid half-life was pronounced and the nonrenal clearance was markedly increased. These findings indicate that decreased isoniazid clearance in chronic renal failure is caused in minor part by the decreased renal excretion of isoniazid and in major part by the depressed hepatic N-acetylation of isoniazid.