Total Plasma Clearance Research Articles

Integrated Approach of In Vivo and In Vitro Evaluation of the Involvement of Hepatic Uptake Organic Anion Transporters in the Drug Disposition in Rats Using Rifampicin as an Inhibitor

Cumulative studies describe the importance of drug transporters as one of the key determinants of pharmacokinetics that necessitate investigation and assessment of the involvement of drug transporters in drug discovery and development. The present study investigated an integrated in vivo and in vitro approach to determine the involvement of organic anion transporting polypeptides (Oatps) in the disposition of drugs in rats using rifampicin as an inhibitor. When bromosulfophthalein (BSP) and HMG-CoA reductase inhibitors (statins), which were used as model substrates for Oatps, were administered intravenously (3 and 1 mg/kg, respectively) to rats pretreated with rifampicin orally (30 mg/kg), the total plasma clearance of BSP and statins was attenuated compared with that in control rats, suggesting the involvement of Oatps in the disposition of these drugs in vivo. On the other hand, the pharmacokinetics of midazolam, used as a model substrate of cytochrome P450 3a (Cyp3a), was unchanged between control rats and rifampicin-pretreated rats. The involvement of Oatps in the disposition of statins observed in vivo was further clarified by employing an in vitro hepatic uptake study and media-loss assay in the presence or absence of 100 μM rifampicin. Hepatic intrinsic clearance was reduced in the presence of rifampicin in both the media-loss assay and hepatocyte uptake study. The present study suggests in vivo investigations in rats using rifampicin together with in vitro investigations with a media-loss assay and/or uptake assay using rat hepatocytes can help determine whether a clinical drug-drug interaction study is necessary in drug development.

New Therapies for Diabetes Management

New Therapies for Diabetes Management

Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats

To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t 1/2) in CRC rats (10.02±0.37μg h mL(-1), 0.30±0.02h, respectively) were significantly lower than that in control rats (13.46±1.20μg h mL(-1), 0.52±0.05h, respectively), whereas total plasma clearance (CLtot) in CRC rats (2.01±0.07L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54±0.14L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20% lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t 1/2 and an increase in CLtot after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.

In silico Prediction of Total Human Plasma Clearance

The prediction of the total human plasma clearance of novel chemical entities continues to be of paramount importance in drug design and optimization, because it impacts both dose size and dose regimen. Although many in vivo and in vitro methods have been proposed, a well-constructed, well-validated, and less resource-intensive computational tool would still be very useful in an iterative compound design cycle. A new completely in silico linear PLS (partial least-squares) model to predict the human plasma clearance was built on the basis of a large data set of 754 compounds using physicochemical descriptors and structural fragments, the latter able to better represent biotransformation processes. The model has been validated using the "ELASTICO" approach (Enhanced Leave Analog-Structural, Therapeutic, Ionization Class Out) based on ten therapeutic/structural analog classes. The model yields a geometric mean fold error (GMFE) of 2.1 and a percentage of compounds predicted within 2- and 3-fold error of 59% and 80%, respectively, showing an improved performance when compared with previous published works in predicting clearance of neutral compounds, and a very good performance with ionized molecules at pH 7.5, able to compare favorably with fairly accurate in vivo methods.

Pharmacokinetics and safety of 6 % hydroxyethyl starch 130/0.4 in healthy male volunteers of Japanese ethnicity after single infusion of 500 ml solution

This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6% hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500ml 6% HES 130/0.4 (Voluven 6%; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30min. Plasma concentration of 6% HES 130/0.4 was highest at end of infusion (5.53±0.55mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14±0.16l/h, 1.12±0.26h, and 9.98±2.38h, respectively, and the volume of distribution was 4.76±0.64l. Mean area under the concentration-time curve was 26.7±3.75mg/mlh. The total amount of HES excreted into urine was 59.4% of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5±0.4g/dl at baseline to 13.8±0.4g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. Single administration of a 500ml solution of 6% HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24h after drug administration, accounting for 96% of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups.

Abstract 2911: SAR125844: a potent and selective ATP-competitive inhibitor of MET kinase

Abstract The tyrosine kinase MET is a membrane receptor that is essential for embryonic development and wound healing in normal cells. Stimulation of MET by its natural ligand, the hepatocyte growth factor (HGF), induces cell proliferation, migration, and invasion. Abnormal MET activation (over-expression of MET protein, amplification or mutations of the MET gene) has been observed in multiple human cancer types. We report herein the discovery of a potent and selective small molecule inhibitor (SAR125844) with potential therapeutic application in cancer patients with deregulated MET-dependent malignancies. Our initial hit identification approach was based on the biochemical screen of an in-house kinase inhibitor biased library where a series of benzimidazole sulfonate derivatives were identified with sub-micromolar MET inhibition. In particular, the initial hit exhibited an IC50 of 140 nM vs MET but it also had strong affinity for CDK9 (IC50= 6 nM), a CDK isoform involved in gene transcription. Chemical modifications of the series to dial out CDK9 affinity and remove potential normal cell cytotoxicity led to a more selective derivative with IC50's of 80nM and 1355nM vs MET and CDK9 respectively. Further sub-structural exploration allowed us to identify a heteorocyclic moiety which was shown by X-ray data to specifically interact with Tyr1230 in a non active conformation of the protein. The resulting highly favourable U-shape mode of binding in MET of representative examples from these series (e.g. IC50= 1nM) was not tolerated in CDK9 (IC50 > 10µM). Final multi-parametric medicinal chemistry optimisation led to SAR125844 with single digit nanomolar antiproliferative activity on MET-amplified cell lines. SAR125844 is highly selective for MET kinase in a panel of 275 kinases tested, with only 5 other protein kinases inhibited at IC50 values below 300 nM. This compound exhibits also satisfactory eADMET in vitro properties and has shown moderate total plasma clearance, large volume of distribution and moderate to long terminal elimination half-life in rats. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2911. doi:1538-7445.AM2012-2911

The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans

The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians. Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg). The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC(0-32 h)) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C(max)) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete. Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.

Marbofloxacin Disposition After Intravenous Administration of a Single Dose in Wild Mallard Ducks (Anas platyrhynchos)

Marbofloxacin, a fluoroquinolone developed specifically for veterinary use, has demonstrated considerable pharmokinetic variation among avian species. The goal of this study was to determine the disposition kinetics of marbofloxacin in mallard ducks (Anas platyrhynchos) after a single intravenous injection. Six wild mallard ducks were used in the study. Marbofloxacin was injected at a dose of 2 mg/kg into the basilic vein, and blood was subsequently collected at regular intervals from each bird. Plasma marbofloxacin concentrations were determined by using high-performance liquid chromatography. The volume of distribution at steady state was 1.78 +/- 0.37 L/kg, and the total plasma clearance was 0.59 +/- 0.08 L/kg per hour. Marbofloxacin had a relatively short permanence, with a elimination half-life of 2.81 +/- 1.20 hours, a terminal half-life of 2.43 +/- 0.61 hours, and a mean residence time of 2.99 +/- 0.52 hour. The maximum observed concentration (Cmax) and area under the curve (AUC) were 1.34 +/- 0.27 microg/mL and 3.75 +/- 0.56 microg x h/mL, respectively. Values of minimum inhibitory concentration (MIC), Cmax, and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a Cmax: MIC value of 10 and an AUC: MIC ratio of 125-250 associated with optimal bactericidal effects. By using the study data and MIC breakpoints of 0.125 microg/mL or 0.2 microg/mL, values derived for Cmax: MIC were 9.37 +/- 0.99 and 5.85 +/- 0.62, respectively, and for AUC: MIC were 29.99 +/- 4.51 and 18.74 +/- 2.82, respectively. By using MIC values of 0.125 and 0.2 microg/mL and a target AUC: MIC = 125, the calculated optimal daily marbofloxacin dosages for mallard ducks were 9.24 and 14.78 mg/kg, respectively. These results suggest that, primarily because of the high total plasma clearance observed, the marbofloxacin dose for treatment of bacterial diseases in mallard ducks should be increased after intravenous administration. Intravenous doses of 10-15 mg/kg should be assessed by studying their potential toxicity and efficacy in sick birds.

Metabolism of oxycodone in human hepatocytes from different age groups and prediction of hepatic plasma clearance.

Oxycodone is commonly used to treat severe pain in adults and children. It is extensively metabolized in the liver in adults, but the maturation of metabolism is not well understood. Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool) and predict hepatic plasma clearance of oxycodone using these data. Oxycodone (0.1, 1, and 10 μM) was incubated with hepatocytes for 4 h, and 1 μM oxycodone also with CYP3A inhibitor ketoconazole (1 μM). Oxycodone and noroxycodone concentrations were determined at several time points with liquid chromatography–mass spectrometry. In vitro clearance of oxycodone was used to predict hepatic plasma clearance, using the well-stirred model and published physiological parameters. Noroxycodone was the major metabolite in all batches and ketoconazole inhibited the metabolism markedly in most cases. A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed. The predicted hepatic plasma clearances were typically much lower than the published median total plasma clearance from pharmacokinetic studies. The data suggests that there are no children-specific metabolites of oxycodone. Moreover, CYP3A activity seems to be the major determinant in metabolic clearance of oxycodone regardless of age group or individual variability in hepatocyte batches.

Tramadol--the impact of its pharmacokinetic and pharmacodynamic properties on the clinical management of pain.

Tramadol (CAS 36282-47-0) plays an important role in the management of pain. With its dual mechanism of action (opioid agonist; weak noradrenaline and serotonin reuptake inhibitor) tramadol provides a kind of combined/adjuvant pain therapy. Besides its proven clinical efficacy tramadol is a safe drug as respiratory depression, cardiovascular side effects, drug abuse and dependence are of minor clinical relevance, unlike some other opioids. Following oral administration the bioavailability of tramadol is high (70-90%) and with new slow release preparations twice daily administration enables effective pain control. Tramadol is characterised by low plasma protein binding (20%) and quite extensive tissue distribution (apparent volume of distribution about 3 l/kg). Elimination is primarily by the hepatic route (metabolism by CYP2D6 to an active metabolite and by CYP3A4 and CYP2B6) and partly by the renal route (up to 30% of dose). Elimination half-lives of the active agents range between 4.5 and 9.5 h and total plasma clearance of tramadol is moderately high (600 ml/min). The interaction potential of tramadol is neglectable, as it does not affect the disposition of other drugs. It should be taken into account that inducers (e.g. carbamazepine) or inhibitors (e.g. quinidine for CY2D6) of drug metabolism might modify the elimination of tramadol. Likewise, if kidney (creatinine clearance below 30 ml/min) or hepatic function is severely impaired, some dosage reduction (approximately by 50%) or extension of the dosage interval should be considered. In conclusion, tramadol is an effective and safe analgesic with a very low interaction potential. Therefore it represents a drug of first choice if moderate to severe pain states have to be treated in pediatric, adult and elderly patients including those with poor cardiopulmonary function.

High Performance Liquid Chromatographic Analysis and Pharmacokinetic Characteristics of ID-7181, a Novel Quaternary Ammoniopropenyl Cephalosporin, Following Intravenous and Intramuscular Injections to Rats

The purpose of the present study was to examine the pharmacokinetic characteristics of 7-[(z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[(E)-3-(E)-(1-carbamoyl-1-propene-3-yl) 3-ethylmethylammonio]-1-propene- 1-yl]-3-cepheme-4-carboxylate (CAS 206126-08-1, ID-7181), a novel quaternary ammoniopropenyl cephalosporin that contains two vinyl groups at the C-3 side chain, after being administered intravenously (i.v.) or intramuscularly (i.m.) to rats. An HPLC-based method was developed to analyze the ID-7181 levels in the plasma, bile, urine, feces, and tissue homogenates and validated in a pharmacokinetic study. The plasma concentration of ID-7181 decreased to below the quantifiable limit at 6 h after the i.v. administration to rats following doses of 2-10 mg/kg, yielding a t(1/2,beta) of 77.7-81.7 t(1/2) after i.m. doses of 10-50 mg/kg were 79.3-127 min. The total plasma clearance (CLt) decreased with the nonlinear pharmacokinetics with an increase in the i.m. dose from 10 to 50 mg/kg in rats, while it was not significantly altered after the i.v. dose. The bioavailability of the i.m. administered ID-7181 was 43-63 %. Of the various tissues tested, ID-7181 was mainly distributed in the kidney after the i.v. or i.m. administration. The ID-7181 concentrations in the kidney 0.5 h after being administered i.v. or i.m. were comparable to the plasma concentrations shortly after being administered i.v. or the Cmax after being administered i.m. However, the ID-7181 concentrations in the tissues 6 h after being administered i.v. or i.m. decreased to low i.m. were 35-45 % of the initial doses. The corresponding values in the bile 6 h after being administered i.v. or i.m. were 0.5-1% of the initial dose. In conclusion, ID-7181, administered i.v. or i.m., is mainly distributed to the kidney. By 6 h after i.v. or i.m. administration, the ID-7181 concentrations in the various tissues decreased to very low levels. Moreover, the majority of ID-7181 appeared to be excreted in the urine.

Empagliflozin, a novel selective sodium glucose cotransporter‐2 (SGLT‐2) inhibitor: characterisation and comparison with other SGLT‐2 inhibitors

Empagliflozin is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study assessed pharmacological properties of empagliflozin in vitro and pharmacokinetic properties in vivo and compared its potency and selectivity with other SGLT-2 inhibitors. [(14)C]-alpha-methyl glucopyranoside (AMG) uptake experiments were performed with stable cell lines over-expressing human (h) SGLT-1, 2 and 4. Two new cell lines over-expressing hSGLT-5 and hSGLT-6 were established and [(14)C]-mannose and [(14)C]-myo-inositol uptake assays developed. Binding kinetics were analysed using a radioligand binding assay with [(3)H]-labelled empagliflozin and HEK293-hSGLT-2 cell membranes. Acute in vivo assessment of pharmacokinetics was performed with normoglycaemic beagle dogs and Zucker diabetic fatty (ZDF) rats. Empagliflozin has an IC(50) of 3.1 nM for hSGLT-2. Its binding to SGLT-2 is competitive with glucose (half-life approximately 1 h). Compared with other SGLT-2 inhibitors, empagliflozin has a high degree of selectivity over SGLT-1, 4, 5 and 6. Species differences in SGLT-1 selectivity were identified. Empagliflozin pharmacokinetics in ZDF rats were characterised by moderate total plasma clearance (CL) and bioavailability (BA), while in beagle dogs CL was low and BA was high. Empagliflozin is a potent and competitive SGLT-2 inhibitor with an excellent selectivity profile and the highest selectivity window of the tested SGLT-2 inhibitors over hSGLT-1. Empagliflozin represents an innovative therapeutic approach to treat diabetes.

Competitive binding to plasma thyroid hormone transport proteins and thyroid disruption by phenylbutazone used as a probe

A model of thyroidectomized sheep intravenously supplemented with thyroid hormone (TH) was developed to mimic endogenous TH exposure and to analyze the impact on plasma TH homeostasis of xenobiotic interference with TH binding to plasma proteins. TH was displaced from plasma protein binding sites by using phenylbutazone (PBZ) as a test xenobiotic, to compare the effect of PBZ on steady state free and total plasma TH concentrations between the in vivo situation and an in vitro system. While PBZ increased free TH in vitro, PBZ administration in vivo produced an immediate reduction in both total and free plasma TH. The decrease in the total TH was consistent with a PBZ-induced displacement of TH from its plasma binding proteins, leading to an increase in total TH plasma clearance. However, this reduction in total TH was not expected to be accompanied by a parallel decrease in free plasma TH since the free TH is determined by the clearance of the free plasma TH. This suggested that PBZ may also have interfered with the clearance mechanisms of free TH. It can be concluded that our thyroidectomized sheep model enables a dual action of a xenobiotic on plasma TH to be distinguished, namely a displacement of TH from its binding proteins leading to a decrease in the total plasma concentration, which is not relevant to thyroid function versus an interference with the intrinsic TH clearance leading to a change in the free plasma TH, which has a major impact in terms of thyroid disruption.

Preclinical Pharmacology and Pharmacokinetics of AZD3783, a Selective 5-Hydroxytryptamine 1B Receptor Antagonist

The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.

Influence of water deprivation on the disposition of paracetamol.

The effect of acute (96 h) water deprivation on the disposition of paracetamol (acetaminophen) has been examined in male Sprague-Dawley rats. Plasma and urinary concentrations of the drug and its two major metabolites, the glucuronide and sulphate, were determined by a sensitive and specific high performance liquid chromatographic assay. Following an intravenous dose of 100 mg kg-1 of paracetamol, no significant changes were found in the elimination rate constant (k), the mean residence time (MRT), total plasma clearance (Cl) and the apparent volume of distribution at steady-state (Vss). However, rats deprived of water for 96 h excreted a larger percentage of the administered dose as the glucuronide conjugate (15.3 vs 7.9%) and a smaller percentage as unchanged paracetamol (7.3 vs 20.7%) in the urine. In addition, there was a significant two-fold increase in the partial metabolic clearance to paracetamol glucuronide. Water deprivation also led to a significant reduction in the renal clearance of paracetamol accompanied by an increase in the renal clearance of the glucuronide.

Peripheral Pharmacokinetic Handling and Metabolism of L-Dopa in the Rat: The Effect of Route of Administration and Carbidopa Pretreatment

The effect of carbidopa (L-alpha-methyldopa hydrazine; 25 mg kg-1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxyphenylalanine (L-dopa; 50 mg kg-1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-infinity) after L-dopa i.a. and increased AUC0-infinity after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Interspecies Pharmacokinetic Scaling of Some Iodinated Organic Acids

We have investigated the possibility of interspecies scaling of relationships between the structure and total plasma clearance in a group of nine organic acids (iododerivatives of benzoic, phenylacetic and hippuric acids) in rabbits, rats and mice. The intercompound comparison established the dependence of total plasma clearance predominantly on the molecular structure in all the animals under study, but the dependence on drug lipophilicity was also meaningful. For interspecies scaling of total plasma clearance, the use of a biological clock with an effective renal plasma flow as the unit seemed most suitable and is probably connected with the principal role of the kidney in the elimination of the compounds under study.

Renal excretion of rhodamine 123, a P-glycoprotein substrate, in rats with glycerol-induced acute renal failure.

To clarify renal handling of rhodamine 123, a substrate for P-glycoprotein, in normal and diseased states, in-vivo clearance studies were performed with normal rats and rats with glycerol-induced acute renal failure. For normal rats the excretion ratio of unbound rhodamine 123-to-inulin was 3.25, indicating the presence of the renal tubular secretion of rhodamine 123. Co-administration of cyclosporin, a P-glycoprotein inhibitor, significantly reduced tubular secretion of rhodamine 123. Administration of glycerol induced both an increase in blood urea nitrogen and a reduction in the glomerular filtration rate, confirming the induction of acute renal failure. Total plasma, renal, and tubular secretory clearances of rhodamine 123 were significantly lower for rats with acute renal failure than for control rats. There was no difference between the ATP content of the renal cortex in control rats and those with acute renal failure. In addition to the decrease in renal clearance, a decrease in the biliary clearance of rhodamine 123 was also observed in rats with acute renal failure. These results imply that rhodamine 123 is secreted via P-glycoprotein in renal tubules and that the renal secretory clearance of rhodamine 123 was reduced after acute renal failure, probably because of impairment of P-glycoprotein.

Biodistribution of cyclosporin encapsulated in liposomes modified with bioadhesive polymer.

The purpose of this investigation was to study the possibility of renewing the immunosuppressive activity of cyclosporin by formulating the compound in liposomes modified with bioadhesive polymers. The liposomes prepared were evaluated both pharmacokinetically and pharmacodynamically. Tissue distribution and plasma pharmacokinetics of cyclosporin and model dye, sudan black, which is as hydrophobic as cyclosporin, were studied in rats after intravenous infusion (10 mg kg-1). The immunosuppressive efficacy of liposomal cyclosporin preparations was studied in the allogenic rat-heart-transplantation model, where cyclosporin therapy (10 mg kg-1) continued for one week. The entrapment of sudan black in liposomes modified with bioadhesive polymers resulted in higher sudan black delivery to the spleen and the liver than with standard sudan-black-loaded liposomes. Among the modified liposomes, those modified with carbopol 941 showed the most remarkable enhancing effect on the delivery of sudan black to these organs and total plasma clearance of sudan black decreased to 38.6 +/- 7.8 mL h-1 kg-1 (standard liposomes, 58.9 +/- 6.4 mL h-1 kg-1). Delivery of cyclosporin to the spleen and the liver was increased approximately twofold by modifying the liposomes with carbopol 941. In the preliminary study on the allogenic rat-heart-transplantation model, the mean survival days of the graft were 18.8 +/- 2.9 days for the group receiving cyclosporin liposomes modified with carbopol 941, 14.2 +/- 4.4 days for the group receiving standard cyclosporin liposomes and 7.6 +/- 0.5 days for the group receiving cyclosporin solution. The encapsulation of cyclosporin in liposomes modified with bioadhesive polymer enhanced the residence time of cyclosporin in the systemic circulation, resulting in approximately twofold greater delivery of cyclosporin to the spleen and liver. However, in the allogenic rat-heart-transplantation model no significant difference was detected between the immunosuppressive efficacy of cyclosporin encapsulated in bioadhesive polymer-modified liposomes and that encapsulated in standard liposomes.

Pharmacokinetic Profile of Idazoxan in the Beagle Dog

The alpha 2-antagonist idazoxan (2- (2- (1,4-benzodioxanyl))-2-imidazoline) has been given intravenously and orally to five beagle dogs at 1, 3 and 10 mg kg-1 doses. Idazoxan plasma levels were determined by a HPLC method. After intravenous administration, a linear kinetic behaviour was obtained. Half-life and mean residence time values ranged 105.2-117.1 and 138.1-154.0 min, respectively. Total plasma clearance values and volume of distribution at steady state values ranged from 25.6-32.1 (mL kg-1) min-1 and 3.60-4.36 L kg-1, respectively. After oral administration, time to peak values averaged around 1 h. Dose normalized peak concentration values ranged 161-182 ng mL-1. Bioavailability values ranged 60-88%. Low idazoxan bioavailability has been described in other animal species and attributed to a first-pass effect.