Age-related change in tissue-to-plasma partition coefficient of cefazolin for noneliminating organs in the rat

Age-related changes in tissue distribution characteristics of cefazolin, a cephalosporin antibiotic, were examined for noneliminating organs of rats. The in vivo tissue-to-plasma partition coefficients (Kp,vivo) varied markedly among different ages and organs. In particular, muscle and skin acted as reservoirs for cefazolin distribution. There were also marked differences in interstitial fluid space (IS), determined using [14C]inulin, among different ages and organs. For muscle and bone, the magnitude of the age-related changes in Kp,vivo of cefazolin and IS was in the order of 1-week-old greater than 7-week-old = 100-week-old greater than 50-week-old rats. This is well correlated with the age-related changes in the volume of distribution at the steady state of cefazolin per body weight (Vdss/BW) and the extracellular fluid volume per body weight (Vecw/BW) determined previously using [14C]inulin. The predicted Kp value (Kp,pred) was estimated by incorporating the serum protein binding parameters of cefazolin, the IS values, and an interstitial-to-plasma albumin concentration ratio (AR) into equations derived from an extracellular fluid model. The Kp,pred values exhibited a fairly good correspondence with the Kp,vivo values determined for various organs, except gut, in rats of all four ages. These results suggest that the determinant of the age-related change in Vdss/BW is the difference in the IS value of muscle and bone, while the age-related change in serum protein binding plays only a modest role.     

Effect of sulfaphenazole on tolbutamide distribution in rabbits: analysis of interspecies differences in tissue distribution of tolbutamide

The effect of sulfaphenazole on the distribution of tolbutamide was examined by comparing the change in the steady-state volume of distribution (Vdss) determined from in vivo plasma elimination with the tissue-to-plasma concentration ratio of various tissues (Kp) in rabbits; this effect was compared with that previously reported in rats. In rabbits, the Kp values of six tissues studied (i.e., brain, heart, spleen, small intestine, muscle, and skin) increased in the presence of sulfaphenazole ; except for brain, lung, and adipose tissue, the tissue-to-plasma unbound concentration ratio (Kp,f) of other tissues did show a significant decrease. This suggested that both the tissue and plasma protein binding of tolbutamide were affected by sulfaphenazole and that the increase in Kp was due mainly to the displacement of plasma protein binding of tolbutamide by sulfaphenazole , which was greater than that of tissue binding, while no change in Kp was due to a parallel change in both the plasma protein binding and tissue binding of tolbutamide. In both rabbits and rats, the Vdss calculated from plasma concentration versus time curve was very close to that calculated from the Kp values and volumes of various tissues in the presence and absence of sulfaphenazole , respectively. The interspecies difference of the effect of sulfaphenazole on the tissue distribution of tolbutamide between rabbits and rats was elucidated from both in vivo tissue distribution and in vitro plasma protein binding studies.     

Tissue distribution of terbinafine in rats.

Terbinafine is an allylamine antifungal agent that is highly lipophilic and keratophilic. The aim of this study was to investigate terbinafine distribution in peripheral and visceral tissues after intravenous administration to rats. Terbinafine, 6 mg/kg, was administered to 33 male Sprague-Dawley rats via a jugular vein cannula over 30 s. Groups of 3 rats were sacrificed at each of 11 time points (up to 24 h), and plasma and tissues were dissected, sampled, and analyzed by high-performance liquid chromatography. Terbinafine plasma concentrations declined in a triexponential fashion, with an estimated elimination half-life of 10 h. The estimated clearance of terbinafine in rats was 2 L/h/kg and the volume of distribution at steady state was 6 L/kg. The tissue-to-plasma partition coefficient (K(p)) of terbinafine for different tissues was calculated using the ratio of the area under the curve of concentration-time for tissues (AUC(tissue)) to that for plasma (AUC(plasma)), by parametric and semiparametric approaches. There was good agreement between K(p) estimates determined by different approaches. The preferential distribution of terbinafine to adipose and skin (K(p) = 49 and 45, respectively) was consistent with the lipophilicity of the drug. Uptake of terbinafine into brain (K(p) = 1.3) and muscle (K(p) = 1.0) was significantly lower. In conclusion, terbinafine displays extensive uptake to peripheral tissues, which contributes to the long elimination half-life of this drug.     

Effect of fat tissue volume on the distribution kinetics of biperiden as a function of age in rats

The relationship between the volume of fat tissue and variations in the time course of plasma biperiden concentration in rats has been examined in three different groups (4-, 10-, and 50-week-old rats). The plasma concentrations at 24 hr after iv injection of 3.2 mg/kg varied between 0.8 ng/ml (4-week-old rats) and 5.0 ng/ml (50-week-old rats). The rank order of the steady state distribution volume of biperiden was: 50-week-old rats greater than 10-week-old rats greater than 4-week-old rats. The fat volume of the whole body, extracted from the dried carcass with ether, varied between 42 g/kg (4-week-old rats) and 167 g/kg (50-week-old rats). There was a good correlation between the steady state distribution volume of biperiden per lean mass body weight and the fat volume per lean mass body weight (r = 0.987). The fat/plasma concentration ratios at 8 hr after the iv injection varied between 600 (4-week-old rats) and 200 (50-week-old rats), whereas the brain/plasma concentration ratios were identical to those at steady state among the three groups. The time courses of biperiden concentration in plasma, brain, and fat were simulated using a physiological pharmacokinetic model. There was reasonable agreement between the model predictions and the observed data, suggesting that the change in the fat volume is a dominant determinant of the distribution volume of biperiden in rats. Age-related changes in tissue and plasma concentrations are discussed in relation to the clinical usefulness of the blood level monitoring.     

Constant-rate infusion of nicotine and cotinine. I. A physiological pharmacokinetic analysis of the cotinine disposition, and effects on clearance and distribution in the rat

The tissue partition of cotinine was measured by a GC-MS method following a 6-day constant-rate input of nicotine and cotinine to male rats by means of an osmotic minipump. The tissue-to-blood partition coefficients of cotinine were calculated for adipose (0.08), brain (0.48), heart muscle (0.51), following the cotinine infusion. When nicotine was infused the tissue partitioning of cotinine increased by a factor of 2.3-4.9, depending on the tissue sampled. Another group of animals were killed at timed intervals from 10 min to 30 hr, after having received a single intravenous bolus dose of 0.5 mg cotinine, and the washout of cotinine was traced in blood and tissues. A physiological model was used to simulate the disposition of cotinine. Generally, the model-predicted concentrations were consistent with those found experimentally. The fractional uptake of cotinine into various tissues was simulated. Blood, intestinal, and skeletal muscle tissues embodied more than 70% of the total body load of the drug. Clearance (Cl), volume of distribution (Vd), and the biological half-life (t1/2) were calculated both from the infusion study and by fitting a monoexponential model to the iv blood data of the rat. Significant differences were found in the apparent clearance calculated from the single iv bolus dose compared to the constant rate infusion. The volume of distribution was, however, consistent from both studies. The impact of a change in clearance was also simulated.     

Effects of chronic ethanol ingestion on pharmacokinetics of procainamide in rats

Blood level studies were carried out in rats to determine the effects of chronic ethanol ingestion on the distribution pharmacokinetic parameters and tissue steady-state partition coefficients of procainamide. The ethanol-treated rats received 4g/kg of ethanol daily for 28 days in Treatment A and 4 g/kg of ethanol for an initial 7 days, followed by 8 g/kg of ethanol for the subsequent 21 days in Treatment B; the control rats received isocaloric sucrose in the respective groups. As determined from two-compartment analysis of the blood level data, both ethanol treatments significantly decreased the distribution clearance (CLd; k12Vdc) and the apparent first-order rate constant for drug transfer from the central compartment to the tissue compartment (k12) of procainamide without affecting the total body clearance of drug (CL) or the apparent volumes of distribution of drug in the body at steady state (Vdss) and at pseudo-equilibrium (Vd beta). Additionally, the apparent volume of distribution of the drug in the central compartment (Vdc) was 57-62% greater due to both ethanol treatments. Furthermore, the steady-state partition coefficients of the drug were found to be significantly lower in heart and kidneys and greater in fat of the ethanol-treated rats (Treatment B) as compared with those in the control rats. Possible mechanisms are proposed to account for these various effects in light of the known effects of chronic ethanol ingestion on the chemical composition of cell membranes of tissues and organs.     

Effect of phenobarbitone on the distribution and elimination of imipramine in rats

The effect of phenobarbitone on the steady state volume of distribution (Vdss) and the total body blood clearance (CLtot, b) of imipramine and the serum concentration of its metabolite, desipramine was examined. The serum disappearance of imipramine after an 8 mg kg-1 i.v. dose followed a biexponential decline in both control and phenobarbitone-treated rats while the concentration of its metabolite increased in the phenobarbitone-treated rats then rapidly declined compared with that in control rats. Since CLtot,b was nearly equal to the hepatic blood flow (QH), QH may be the rate-determining step of imipramine elimination. In the control rats the Vdss of imipramine was large at 19.9 litre kg-1. In the phenobarbitone-treated rats the pharmacokinetic parameters, biological half-life (t1/2) and Vdss significantly decreased to approximately 23-40% while CLtot,b increased to 126% of those in the control rats, although the latter difference was not statistically significant. The blood-to-plasma concentration ratios (RB) of imipramine and desipramine decreased in the phenobarbitone-treated rats. The urinary excretion ratios of imipramine and desipramine, to the dose of imipramine over 8 h, were less than 1.5% in both groups. These ratios were not significantly changed in the phenobarbitone-treated rats. It was concluded that the significant decrease in t1/2 of the phenobarbitone-treated rats may not be attributed to the changes in CLtot,b and/or in the urinary excretion, but mainly to the decrease in Vdss.     

Pharmacokinetics of capacity-limited tissue distribution of methicillin in rabbits

Single-dose and steady-state studies were carried out in rabbits to characterize the pharmacokinetics of methicillin elimination and tissue distribution. Serum methicillin concentrations after single doses exhibited a biexponential decline with a mean terminal half-life of 27 +/- 5 min. Steady-state volume of distribution (Vdss) decreased twofold as doses increased from 5 to 125 mg/kg, while total clearance was consistent over this dosage range. During steady-state infusions of 8.7-87.2 mg/kg/h, the serum and extravascular fluid concentrations increased in proportion to dose, while clearance remained constant. Methicillin tissue concentrations did not increase in proportion to dose and serum concentration, and the Vdss measured from tissue recovery decreased as dosage and serum concentrations increased. Central compartment volume and serum protein binding did not change. The cause of the dose-dependent change in Vdss was a capacity-limited uptake of methicillin into essentially all nonexcretory tissues. This process was described by a partial physiological pharmacokinetic model based on the actual weights or volumes of the rabbit tissues. Distribution into extracellular fluids was assumed to be complete, while entry into cellular, nonexcretory tissue became capacity limited as the Km (17.2 micrograms/mL) was exceeded. The result was a decline in Vdss with increasing serum concentrations to a limiting value which approached the volume of the central space (Vc) and was similar to the extracellular water volume of the rabbit (0.17 L/kg). In the dosage range where total clearance was independent of serum concentration, the distribution of methicillin was concentration dependent and could be predicted by equations derived from the Michaelis-Menten equation.     

Pharmacokinetic profile of two aromatic retinoids (etretinate and acitretin) in the obese Zucker rat

Etretinate accumulates in adipose tissue; this appears to account for its long terminal elimination phase in psoriatic patients. The purpose of the present study was to investigate the pharmacokinetic profile of etretinate and acitretin in a genetically obese rodent model, the Zucker rat. Pairs of obese and lean Zucker rats were dosed intravenously (0.5 mg/kg) and blood samples were collected. Plasma concentrations of etretinate and its major metabolites, acitretin and the cis isomer of acitretin (isoacitretin), were assayed by HPLC. The systemic clearance (CLs) of etretinate and the formation clearance (CLf) of the metabolite (acitretin) were lower in the obese rats (132 and 62.4 mL/min, respectively) compared with their lean littermates (197 and 126 mL/min, respectively). The remaining metabolic clearance (CLd) was identical for the lean and obese animals (70.9 and 69.9 mL/min, respectively). The ratio of metabolite-to-parent drug area under the plasma concentration-time curve (i.e., acitretin:etretinate) in the obese animal was less than that value in the lean animals (0.348 versus 0.811, respectively) following the administration of etretinate. Despite a doubling in the mean value (204 versus 87.9 mL), no statistically significant differences in the volume of distribution term for etretinate (Vdss) was observed in the obese animals, due to the large interanimal variability. The terminal phase half-life (t1/2) was significantly longer in the obese rats (3.52 versus 1.25 h). Following acitretin administration, no statistically significant differences were observed between the obese and lean animals for any of the parameters (CLs, Vdss, MRT, t1/2) of acitretin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiologically based pharmacokinetic modeling of SNU-0039, an anti-Alzheimer’s agent,in rats

The objective of this study was to characterize the systemic and tissue kinetics of 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (SNU-0039), an inhibitor of β-amyloid protein aggregation, in rats. Simultaneous fitting of the data to polyexponential equations indicated that the systemic clearance and steady state volume of distribution were estimated to be 0.0220 l/min/kg and 2.33 l/kg. The clearance and volume of distribution were not dependent on the intravenous dose, in the range from 5 to 20 mg/kg. The tissue (i.e., the brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose tissue) to plasma partition coefficients (K _p ) for SNU-0039 in rats ranged from a low of 0.779 ± 0.314 (muscle) to a high of 5.71 ± 1.66 (liver). The recoveries of DMB were less than 1% of the dose for the renal and biliary excretion, indicative of minor involvements of these pathways in overall elimination. The fraction of bound SNU-0039 to plasma protein was approximately 95.9% and the fraction of SNU-0039 distributed to blood cells was approximately 45.3%. Assuming a flow-limited distribution, the simulated concentration profiles for SNU-0039 in the physiologically based pharmacokinetic model were in reasonable agreement with the observed concentrations in plasma and nine tissues in rats.     

Physiologically based pharmacokinetics of drug-drug interaction: A study of tolbutamide-sulfonamide interaction in rats

A blood flow rate-limited pharmacokinetic model was developed to study the effect of sulfonamide on the plasma elimination and tissue distribution of¹⁴C -tolbutamide (TB) in rats. The sulfonamides (SA) used were sulfaphenazole (SP), sulfadimethoxine (SDM), and sulfamethoxazole (SMZ). The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e., lung, liver, heart, kidney, spleen, G.I. tract, pancreas, brain, muscle, adipose tissue, and skin, increased in the presence of SA, but except for brain, liver, and spleen, the tissue-to-plasma unbound concentration ratio (Kp, f) of other tissues did not show a significant alteration. This suggested that the tissue binding of TB is not affected by SA and that the increase of Kp is due mainly to the displacement of plasma protein-bound TB by SA. The concentrations of TB in several tissues and plasma were predicted by a physiologically based pharmacokinetic model using in vitro plasma binding and metabolic parameters, the plasma-to-blood concentration ratio and the tissue-to-plasma unbound concentration ratios having been determined from both the tissue and plasma concentrations of TB at the β-phase after intravenous administration of TB and the plasma free fraction. The predicted concentration curves of TB in each tissue and in plasma showed good agreement with the observed values except for the brain, for which the predicted concentrations were lower than the observed values in the early time period. In the SP- and SDM-treated rats, the predicted free concentration of TB in the target organ, the pancreas, at 6 h was six times higher than that of the control rats. From these findings, it is suggested that physiologically based pharmacokinetic analysis could be generally useful to predict approximate plasma and tissue concentrations of a drug in the presence of drug-drug interaction.     

Structure-tissue distribution relationship based on physiological pharmacokinetics for NY-198, a new antimicrobial agent, and the related pyridonecarboxylic acids

Comparative physiological pharmacokinetic analysis has been carried out to elucidate the different tissue distribution characteristics among eight pyridonecarboxylic acids including newly developed NY-198. The urinary and fecal recoveries of NY-198 were 76.3 +/- 1.3% and 21.0 +/- 0.1% of the dose (mean +/- SE, N = 3), respectively, after the iv administration of [14C]NY-198 as a 20 mg/kg dose. Model-independent moment analysis of the serum concentration-time profile of [14C]NY-198 gave the volume of distribution at steady state per body weight (Vdss/BW) as 1150 ml/kg. Intrinsic renal clearance (CLint.kd) and intrinsic hepatic clearance (CLint.lv) were estimated to be 7.68 ml/min/kg and 6.33 ml/min/kg, respectively, by the cumulative urinary recovery and the area under the curve of the serum concentration-time profile of NY-198 and the blood flow rate. The tissue-to-serum partition coefficients (Kp) were determined from the analysis of the tissue and serum concentration-time profiles after iv bolus or infusion of nalidixic acid, NY-198, and its structural analogue NY-239. These values were also determined from the analysis of similar data reported in the literature for the other pyridonecarboxylic acids (enoxacin, miloxacin, ofloxacin, pefloxacin, and pipemidic acid). The Kp values of NY-198 ranged from 0.22 to 4.85 and were very similar to those for ofloxacin, being the highest in the disposing organs, kidneys and liver, the lowest in fat and brain, and modest in the other nondisposing organs. A good correlation (r = 0.981) was obtained between serum unbound fraction (fp) and the steady state distribution volume per body weight (Vd(ss)/BW), which was determined from the tissue partition coefficient. Additionally, comparatively good correlations were also obtained between fp and the Kp or apparent tissue-to-serum concentration ratio (Kp,app). Thus, the difference of serum unbound fraction has been demonstrated for the determining factor of the structure-dependent tissue distribution difference, whereas the tissue binding has been suggested to be only slightly different for respective tissues among PCA derivatives. The concentration-time profile for serum and tissues (lung, heart, muscle, kidney, liver, spleen, gut, bone, skin, and brain) was predicted for NY-198 by physiological pharmacokinetics using the averaged tissue-to-serum unbound concentration ratio (Kp,f) which was determined from the Kp,f of eight PCA analogues.(ABSTRACT TRUNCATED AT 400 WORDS)     

Analysis of nonlinear tissue distribution of quinidine in rats by physiologically based pharmacokinetics

The nonlinear tissue distribution of quinidine in rats was investigated by a physiologically based pharmacokinetic model. Serum protein binding of quinidine showed a nonlinearity over the in vivo plasma concentration range. The blood-to-plasma concentration ratio (Cb/Cp) of quinidine also showed a concentration dependence. The steady-state volume of distribution (Vss) determined over the plasma concentration range from 0.5 to 10 micrograms/ml was 6.0 +/- 0.45 L/kg. The tissue-to-plasma partition coefficient (Kp) of muscle, skin, liver, lung, and gastrointestinal tract (GI) showed a nonlinearity over the in vivo plasma concentration range of quinidine, suggesting saturable tissue binding. The concentration of quinidine in several tissues and plasma was predicted by a physiologically based pharmacokinetic model using in vitro plasma protein binding and the Cb/Cp of quinidine. The tissue binding parameters were estimated from in vivo Kp values. The predicted concentration curves of quinidine in each tissue and in plasma showed good agreement with the observed values.     

Interindividual changes in volume of distribution of cefazolin in newborn infants and its prediction based on physiological pharmacokinetic concepts

The purpose of this study was to investigate factors affecting the volume of distribution of cefazolin (a beta-lactam antibiotic) in newborn infants with bacterial infections, and to propose a method for predicting the volume of distribution at steady state per body weight (Vdss/BW). Cefazolin and tobramycin (an aminoglycoside) were simultaneously given to newborn infants (aged 2 to 28 d), and plasma concentration-time data were analyzed on the basis of model-independent moment analysis. The Vdss/BW values ranged from 0.212 to 0.373 L/kg for cefazolin and from 0.384 to 0.541 L/kg for tobramycin. The unbound fraction of cefazolin in plasma (fp) fluctuated widely, from 0.22 to 0.83, among patients. The Vdss/BW value for cefazolin was characterized by both large extracellular water volume and a remarkable change in fp, and could be predicted as a function of fp using physiological pharmacokinetic concepts. Moreover, interindividual changes in the unconjugated bilirubin:albumin molar ratio were predominantly responsible for the individual variation in the fp values of cefazolin in newborn infants.     

A physiologically based pharmacokinetic model for (-)-quinuclidinyl benzylate using nonlinear irreversible tissue binding parameters in rats.

The disposition characteristics of (-)-quinuclidinyl benzylate (QNB) were investigated in rats, and a physiologically based pharmacokinetic model was established using its linear and nonlinear tissue binding parameters. The steady-state distribution volume (Vdss) and systemic clearance (CLtot) were comparable after iv administration of 325 ng/kg and 3.2 mg/kg, suggesting that QNB pharmacokinetics based on plasma concentrations is linear. However, tissue accumulation was observed in the heart, lung, muscle, and brain. This accumulation persisted for over 12 hr after the iv administration of 325 ng/kg [3H]QNB. Tissue binding parameters were determined after continuous infusion of QNB. Irreversible and nonlinear binding parameters were obtained in various regions of the brain and other tissues. Reversible equilibrium concentration ratios between tissue and plasma were determined after high-dose infusion. QNB concentrations in the plasma, heart, lung, muscle, and brain were predicted after the administration of 325 ng/kg or 3.2 mg/kg. There was reasonable agreement between the model predictions and the observed data.     

Kinetics of distribution and adipose tissue storage as a function of lipophilicity and chemical structure. I. Barbiturates.

Distribution kinetics of 5-ethyl-substituted oxy-, N-alkyl-, and thiobarbiturates covering a range of partition coefficients of octanol/water (log P 1.6 to 4.1) were determined in rats. Concentration-time curves for plasma, adipose tissue, liver, and muscle after single iv administration were obtained using HPLC analysis. Pharmacokinetic parameters were calculated for plasma and tissues. A physiological pharmacokinetic model allowed the simulation and prediction of adipose tissue kinetics based on blood and plasma kinetics, adipose tissue/plasma distribution coefficient, volume and perfusion rate of adipose tissue. Adipose tissue storage was quantified with the adipose storage index (ASI). Including data of barbiturates from the literature, the correlation between ASI and log P was poor except for oxybarbiturates not substituted in N1. Within comparable log P ranges, ASI values increased from oxy- to N-alkylated to thiobarbiturates. Thus, even within the chemical class of barbiturates log P is not a sufficient criterion for adipose tissue storage. Rather, adipose tissue storage is influenced by individual functional groups.     

Constant-rate infusion of nicotine and cotinine. I. A physiological pharmacokinetic analysis of the cotinine disposition,and effects on clearance and distribution in the rat

The tissue partition of cotinine was measured by a GC-MS method following a 6-day constant-rate input of nicotine and cotinine to male rats by means of an osmotic minipump. The tissue-to-blood partition coefficients of cotinine were calculated for adipose (0.08), brain (0.48), heart muscle (0.55), intestinal (0.53), hepatic (0.64), pulmonary (0.50), renal (0.99), and skeletal muscle tissue (0.51), following the cotinine infusion. When nicotine was infused the tissue partitioning of cotinine increased by a factor of 2.3–4.9, depending on the tissue sampled. Another group of animals were killed at timed intervals from 10 min to 30 hr, after having received a single intravenous bolus dose of 0.5 mg cotinine, and the washout of cotinine was traced in blood and tissues. A physiological model was used to simulate the disposition of cotinine. Generally, the model-predicted concentrations were consistent with those found experimentally. The fractional uptake of cotinine into various tissues was simulated. Blood, intestinal, and skeletal muscle tissues embodied more than 70% of the total body load of the drug. Clearance (Cl),volume of distribution (V_d),and the biological half-life (t_1/2)were calculated both from the infusion study and by fitting a monoexponential model to the iv blood data of the rat. Significant differences were found in the apparent clearance calculated from the single iv bolus dose compared to the constant rate infusion. The volume of distribution was, however, consistent from both studies. The impact of a change in clearance was also simulated.The financial support from the Brown and Williamson Tobacco Company (USA) and the Åke Wiberg Foundation (Sweden) is gratefully acknowledged.     

Pharmacokinetics of lurasidone, a novel atypical anti-psychotic drug, in rats

This study aimed to characterise the pharmacokinetics of lurasidone, a new atypical anti-psychotic drug, in rats after intravenous and oral administration at dose range 0.5-2.5 and 2.5-10?mg/kg, respectively. Moreover, tissue distribution, liver microsomal stability and plasma protein binding were estimated. After intravenous injection, systemic clearance, steady-state volumes of distribution and half-life remained unaltered as a function of dose with values in the range 22.1-27.0?mL/min/kg, 2,380-2,850?mL/kg and 229-267?min, respectively. Following oral administration, absolute oral bioavailability was not dose dependent with approximately 23%. The recoveries of lurasidone in urine and bile were 0.286% and 0.0606%, respectively. Lurasidone was primarily distributed to nine tissues (brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose) and tissue-to-plasma ratios of lurasidone were ranged from 1.06 (brain) to 9.16 (adipose). Further, lurasidone was unstable in rat liver microsome and the plasma protein binding of lurasidone was concentration independent with approximately 99.6%. In conclusion, lurasidone showed dose-independent pharmacokinetics at an intravenous dose of 0.5-2.5?mg/kg and an oral dose of 2.5-10?mg/kg. Lurasidone was primarily distributed to nine tissues and appeared to be primarily eliminated by its metabolism.     

Effect of uraemia and anephric state on the pharmacokinetics of tenoxicam in the rat.

Renal alterations, uraemia and nephrotic syndrome induced in experimental animals caused a reduction in the plasma albumin concentration of 25 and 30%, respectively. As a result of this decrease, the unbound fraction of tenoxicam in uraemic rats (0.06 +/- 0.02) and in anephric rats (0.11 +/- 0.08) increased with respect to the control group (0.03 +/- 0.004). The induced hypoalbuminaemia did not modify the blood to plasma concentration ratio. Both plasma clearance (CL) and apparent volume of distribution at steady-state (Vdss) rose significantly with the increase in the unbound fraction: (Vdss 55 +/- 6 mL (control rats); 69 +/- 12 mL (uraemic rats); 96 +/- 30 mL (anephric rats); CL = 7 +/- 1 mL h-1 (control rats); 12 +/- 4 mL h-1 (uraemic rats); 15 +/- 7 mL h-1 (anephric rats)). Tenoxicam elimination was found to be restrictive, with an extraction ratio less than 0.1 in the three groups. The induction of nephrotic syndrome was observed to have a significant effect on intrinsic metabolic activity, intrinsic clearance of tenoxicam being reduced by 30% in the anephric rats (161 +/- 38 mL h-1) with respect to the values obtained in the control group (228 +/- 22 mL h-1).     

Biperiden effects and plasma levels in volunteers

Summary The pharmacokinetics of biperiden was studied and compared with pharmacodynamics (pupil size, accomodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 h, biperiden was rapidly absorbed with a half-life of 0.3 h, plasma peak levels of 5 ng/ml being reached after 1.5 h. Biperiden showed good tissue penetration (distribution half-life 0.6 h; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 h, and the oral clearance was 146 l/h. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 h (accommodation).Dedicated to Prof. Dr. Ernst Biekert on the occasion of his 60th birthday