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High Clearance (high + clearance)
Selected AbstractsInteraction of Drugs and Chinese Herbs: Pharmacokinetic Changes of Tolbutamide and Diazepam Caused by Extract of Angelica dahuricaJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000KAZUHISA ISHIHARA The inhibitory effects of Angelica dahurica root extract on rat liver microsomal cytochrome P450 and drug-drug interactions were studied. The 2,- and 16,-hydroxylase activity of testosterone were most strongly inhibited, with 17.2% and 28.5% of their activity remaining, respectively, after oral administration of A. dahurica extract at a 1 g kg,1 dose. 6,-Hydroxylase activity was also inhibited, with 70% of its activity remaining, under the same conditions. In addition, treatment with the extract inhibited the metabolism of tolbutamide, nifedipine and bufuralol. These results showed that the extract inhibited the various isoforms of cytochrome P450 such as CYP2C, CYP3A and CYP2D1. The A. dahurica extract delayed elimination of tolbutamide after intravenous administration at a 10 mg kg,1 dose to rats. Thus, the extract altered the liver intrinsic clearance. It had little effect, however, on the pharmacokinetic parameters of diazepam after intravenous administration at 10 mg kg,1. Since diazepam showed high clearance, it underwent hepatic blood flow rate-limited metabolism. Therefore, the change of intrinsic clearance had little effect on hepatic clearance. However, the Cmax value after oral administration of diazepam with extract treatment was four times that with non-treatment. It was suggested that the first-pass effect was changed markedly by the extract. High-dose (1 g kg,1), but not low dose (0.3 g kg,1), administration of A. dahurica extract increased significantly the duration of rotarod disruption following intravenous administration of diazepam at 5 mg kg,1. It was concluded that administration of A. dahurica extract has the potential to interfere with the metabolism, by liver cytochrome P450, of other drugs. [source] Pharmacokinetics of the injectable formulation of methadone hydrochloride administered orally in horsesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009R. L. LINARDI Methadone hydrochloride is a synthetic ,-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/mass spectrometry at predetermined time points for 24 h, and PK parameters were estimated using a noncompartmental model. Physical effects were observed and recorded by experienced clinicians. No drug toxicity, behavioural or adverse effects were observed in the horses. The disposition of methadone followed first order elimination and a biphasic serum profile with rapid absorption and elimination phases. The PK profile of methadone was characterized by high clearance (Cl/F), small volume of distribution (Vd/F) and short elimination half-life (t1/2). The mean of the estimated t1/2 (SD) for each dose (0.1, 0.2 and 0.4 mg/kg) was 2.2 (35.6), 1.3 (46.1) and 1.5 (40.8), and the mean for the estimated Cmax (SD) was 33.9 (6.7), 127.9 (36.0) and 193.5 (65.8) respectively. [source] Role of drug metabolism in drug discovery and developmentMEDICINAL RESEARCH REVIEWS, Issue 5 2001Gondi N. Kumar Abstract Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug,drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug,drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug,drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug,drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397,411, 2001 [source] Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2009Avantika Barve Abstract The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120,min. Based on the values of the kinetic constants (Km and Vmax), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25,mg/kg) or orally (100, 250,mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100,mg/kg kaempferol. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration,time profiles for 10 and 25,mg/kg were consistent with high clearance (,3,L/hr/kg) and large volumes of distribution (8,12,L/hr/kg). The disposition was characterized by a terminal half-life value of 3,4,h. After oral administration the plasma concentration,time profiles demonstrated fairly rapid absorption (tmax,1,2,h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at ,2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. Copyright © 2009 John Wiley & Sons, Ltd. [source] Evaluation of pharmacokinetics, brain levels and protein binding of centpropazine in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2004Venkatesh Atul Bhattaram Abstract The pharmacokinetics of centpropazine (CNPZ), an antidepressant, was studied in rats. CNPZ was administered to groups of rats (n=3 to 5) via oral (40 mg/kg), intravenous (5 mg/kg), intraperitoneal (5 mg/kg) and intraduodenal (4 and 8 mg/kg) routes. The AUCs of CNPZ were estimated and the bioavailabilities were calculated. CNPZ was characterized by a short elimination half-life (39.5 min), a high clearance (118 ml/min/kg) and a relatively large volume of distribution (1945 ml/kg) after intravenous administration. After oral administration CNPZ exhibited a very low oral bioavailability (,0.2%). The total first pass effect (Egit+liver) was calculated as 98.7%. The bioavailability of CNPZ was similar when administered by intraduodenal and oral routes. CNPZ readily penetrated into the brain and reached Cmax by 30 min post oral dosing. About 92.0%±0.8% of the drug was bound to serum proteins. Low oral bioavailability of CNPZ following oral administration is likely due to its metabolism by intestinal mucosa and liver. Copyright © 2004 John Wiley & Sons, Ltd. [source] Disposition of isosteviol in the rat isolated perfused liverCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2010Hongping Jin Summary 1. The aim of the present study was to investigate the mechanisms involved in the clearance of isosteviol using the rat isolated perfused liver. 2. Six livers from male Sprague-Dawley rats were perfused with 15.7 ,mol isosteviol in a recirculating system. Perfusate and bile samples were collected for 60 min and the liver was collected at the end of the perfusion. All samples collected were incubated with ,-glucuronidase. Isosteviol,glucuronide was determined as equivalent isosteviol. Isosteviol concentrations were determined using a previously developed liquid chromatography,tandem mass spectrometry method. The final isosteviol liver/perfusate (L/P), bile/liver (B/L) and isosteviol-glucuronide in bile/liver (BG/LG) ratios were determined. 3. Isosteviol has a high clearance (21.4 ± 4.8 mL/min) from the perfusate, with a short half-life (13 ± 4 min). ,-Glucuronidase incubation revealed that isosteviol is conjugated in the liver and excreted into the bile. There was no isosteviol-glucuronide detected in perfusate samples. The total recovery of the rat isolated perfused liver system is 74 ± 14% and glucuronidated isosteviol accounted for 23 ± 4% of the administered dose. 4. In conclusion, we are the first to characterize the metabolism of isosteviol using rat isolated liver perfusion. Our results strongly suggest that the liver is the main organ of isosteviol elimination and that isosteviol is glucuronidated in the liver before it is excreted into the bile. [source] | ||||||||||