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.     

Pharmacokinetics of amikacin (BB-K8) in patients undergoing hemodialysis.

The pharmacokinetics of Amikacin (BB-K8) was studied after administration in an i.v. bolus injection of 7.5 mg/kg to 10 patients with terminal renal impairment undergoing dialysis sessions of 6 hours. A two-compartment kinetic model has been used to describe the bi-phasic decrease of the plasma concentrations of the antibiotic thus establishing the amounts of the antibiotic in the central and peripheral compartments, its elimination being principally through the kidney. During the hemodialysis sessions the average pharmacokinetic parameters of the Amikacin were: alpha = 3.422 h-1 beta = 0.176 h-1 K12 = 1.820 h-1 K21 = 1.327 H-1, K13 = 0.450 h-1, Vc = 9.242 l Vp = 11.455 l Vdss = 20.697 l and delta = 0.377 l/kg. A dosage regimen as a function of the pharmacokinetic parameters is established for patients with terminal renal impairment which guarantees safe and efficient concentrations of the antibiotic.     

Pharmacokinetics of Amikacin (BB-K8) in patients with normal or impaired renal function.

The pharmacokinetics of Amikacin (BB-K8) were determined after a single i.v. injection of 7.8 mg of the antibiotic/kg of body weight. It was administered to 10 patients with normal renal function and 19 patients with varying degrees of renal impairment. The elimination of Amikacin from plasma was seen to follow the course of an open two-compartment model system. From patients with normal renal function, values for the following pharmacokinetic parameters were obtained: alpha = 4.219 hr-1; beta = 0.292 hr-1; K12 = 2.218 hr-1; K21 = 0.859 hr-1; K13 = 1.432 hr-1; Vc = 3.125 1; Vp = 8.068 1 and Vdss = 11.193 1. As the relationship K12/K21 is greater than 1, it may be seen that there is a tendency for the antibiotic to accumulate in the peripheric compartment. Impaired renal function significantly diminishes the values recorded for alpha, beta, K12, K21, K13. Distribution volumes are significantly increased in patients with renal impairment. A linear relationship between the K13 of Amikacin and creatinine clearance is demonstrated. Adjustment of Amikacin dosage, according to the individual degree of renal impairment, may be obtained by spacing out the injections.     

Physiologically based pharmacokinetic model for beta-lactam antibiotics I: Tissue distribution and elimination in rats

The disposition characteristics of beta-lactam antibiotics in rats were investigated, and a physiologically based pharmacokinetic model capable of predicting the tissue distribution and elimination kinetics of these drugs was developed. Protein-binding parameters in rat serum were determined by equilibrium dialysis. Linear binding was found for penicillin G, methicillin, dicloxacillin, and ampicillin; however, nonlinear binding was observed for penicillin V and cefazolin. After intravenous bolus dosing, cefazolin was recovered almost completely in urine and bile, while for the penicillins, penicilloic acid was found to be the major metabolite. Biliary excretion of cefazolin followed Michaelis-Menten kinetics, and no significant inhibition of urinary secretion was observed after probenecid administration. The renal clearance of unbound drug was 0.82 ml/min with a reabsorption ratio (R) of 0.22. Tubular secretion was inhibited for the penicillins by probenecid plasma concentrations of 50 micrograms/ml, resulting in an R-value of 0.32. Erythrocyte uptake, serum protein binding, and tissue-to-plasma partition coefficient (Kp) were measured. Theoretical Kp values were calculated and found to be in good agreement with the Kp values for three of the antibiotics. Plasma and tissue concentrations (lung, heart, muscle, skin, gut, bone, liver, and kidney) were measured as a function of time at various doses for inulin and cefazolin in rats after an intravenous bolus dose, and were found to be in reasonable agreement with concentrations predicted by the model. These correlations demonstrate that the proposed model can accurately describe the plasma and tissue contributions of inulin and cefazolin in the rat and suggest that this model could have utility in predicting drug distribution in humans.     

Increased levels of protein- and lipid-bound sialic acids in the renal cortex of rats injected with low doses of gentamicin

Administration of the aminoglycoside antibiotic, gentamicin, even at therapeutic doses, causes renal lysosomal phospholipidosis. We now report that protein- and lipid-bound sialic acid levels are increased significantly in a time-dependent fashion in the renal cortex of rats injected with gentamicin (10 mg/kg body wt. per day) for 4-10 days and a significant relationship could be observed between these two parameters. This elevation was not due to tissue regeneration, since it was not observed in cisplatin-treated animals.     

Renal toxicity after chronic inhalation exposure of rats to trichloroethylene

Male Long-Evans rats were exposed to 0 (controls) or 500 ppm trichloroethylene (TRI) for 6 months, 6 h daily, and 5 days a week. The TRI metabolites trichloroethanol (TCE) in blood and trichloroacetic acid (TCA) in urine were measured. Specific parameters related to the renal damage were determined in urine [biomarker for glomerular damage: high molecular weight proteins (HMW), albumin (ALB); for proximal tubular damage: N-acetyl-beta-D-glucosaminidase (NAG), low-molecular-weight-proteins (LMW)]. Significantly increased concentrations of NAG and LMW in urine of exposed rats were detected. No DNA-strand breaks in kidney cells could be detected using the comet assay, and histological examinations were performed. Histological alterations were observed in glomeruli and tubuli of exposed rats. The release of biomarkers for nephrotoxicity suggested alterations preferably in the proximal tubules of the exposed rats.     

REGIONAL BRAIN DOSIMETRY OF TRICHLOROETHANE IN MICE AND RATS FOLLOWING INHALATION EXPOSURES

While certain neuroactive volatile organic compounds (VOCs) have been reported to have an uneven distribution in various anatomically distinctive brain regions, this has not yet been reported for the short-chain aliphatic halogenated hydrocarbons. Therefore, the uptake and regional brain distribution of 1,1,1-trichloroethane (TRI) in mice and rats following inhalation exposure were examined. Male Sprague-Dawley rats and CD-1 mice were exposed to TRI at either 3500 or 5000 ppm for 10, 30, 60, or 120 min. Seven brain regions from rats and three from mice were sampled, and TRI concentrations in the blood and brain tissues were determined by headspace gas chromatography. In both species, the medulla oblongata was found to have the highest TRI concentrations, while cortex (in both species) and hippocampus (only sampled in rats) contained the lowest TRI concentrations. Substantial differences were also observed between the two species, as the mice exhibited higher capacity to accumulate TRI in the blood as well as in the brain regions. It appears that lipid content is a main factor influencing the differential disposition of TRI among the brains regions. Physiological differences in the respiratory systems of the two species and the physiochemical properties of the chemical favoring diffusion toward lipid-rich compartments could also have been expected to account for the patterns of regional distribution and species differences.     

Distribution kinetics of netilmicin in human blister fluid: effect of renal impairment

The pharmacokinetics of netilmicin in plasma and blister fluid were compared in 10 healthy volunteers with normal renal function and 10 voluntary patients with varying degrees of renal impairment. Netilmicin kinetics in plasma were characterized by an open two-compartment kinetic model. For the study of the kinetics of the antibiotic in blister fluid a specific kinetic distribution model was employed. In the healthy volunteers the plasma kinetics of netilmicin showed a behaviour similar to that of other aminoglycoside antibiotics, although a high blister/plasma partition coefficient was obtained, with a mean value of 4.27 +/- 1.65. The transfer of netilmicin in blister fluid governed by the constants K1b/Vb and Kbl had mean values of 0.19 +/- 0.09 h-1 l-1 and 0.25 +/- 0.10 h-1, respectively. In the patients with renal impairment plasma and blister fluid antibiotic levels showed a progressive accumulation. In these patients the affinity of netilmicin for blister fluid was significantly altered. The blister/plasma partition coefficient in this group of patients had a mean value of 2.65 +/- 1.33; the decrease being statistically significant (p = 0.023) with respect to the value obtained in the healthy volunteers. Similarly, the exit constant of netilmicin from blister fluid (Kb1) showed a statistically significant increase (p = 0.035) in the patients with renal impairment. The findings point to a loss of affinity of netilmicin for blister fluid as a result of renal impairment. Linear and logarithmic relationships were established between some pharmacokinetic parameters and creatinine clearance. Dosage schedules are proposed for netilmicin in patients with renal impairment.     

A minimal physiological model of thiopental distribution kinetics based on a multiple indicator approach.

Currently available models of thiopental disposition kinetics using only plasma concentration-time data neglect the influence of intratissue diffusion and provide no direct information on tissue partitioning in individual subjects. Our approach was based on a lumped-organ recirculatory model that has recently been applied to unbound compounds. The goal was to find the simplest model that accounts for the heterogeneity in tissue partition coefficients and accurately describes initial distribution kinetics of thiopental in dogs. To ensure identifiability of the underlying axially distributed capillary-tissue exchange model, simultaneously measured disposition data of the vascular indicator, indocyanine green, and the marker of whole body water, antipyrine, were analyzed together with those of thiopental. A model obtained by grouping the systemic organs in two subsystems containing fat and nonfat tissues, successfully described all data and allowed an accurate estimation of model parameters. The estimated tissue partition coefficients were in accordance with those measured in rats. Because of the effect of tissue binding, the diffusional equilibration time characterizing intratissue distribution of thiopental is longer than that of antipyrine. The approach could potentially be used in clinical pharmacokinetics and could increase our understanding of the effect of obesity on the disposition kinetics of lipid-soluble drugs.     

The influence of amikacin on digoxin uptake by certain rabbit tissues in vitro

The influence of amikacin on digoxin uptake by various rabbit tissues was investigated in vitro. 125J-digoxin was used and radioactivity was counted in a gamma scintillation counter. Amikacin decreases digoxin uptake by the renal tissue and this action is probably due to a displacing effect. On the contrary, amikacin increases digoxin uptake by striated and cardiac muscle. It is suggested that the latter action is due to a vasodilating effect of the aminoglycoside antibiotic that favors the microcirculation of the above tissues.     

Studies of acute nephrotoxic potential of trichloroethylene in Fischer 344 rats

Group of male Fischer 344 rats, after pretreatment with phenobarbital (80 mg/kg, ip, 3 d), were treated ip in corn oil with 0, 5.5, 11.0, and 22.0 mmol trichloroethylene (TRI) per kg body weight. Urines were collected 24 h after the treatment and the animals were then sacrificed. The nephrotoxicity of TRI was then studied by measuring certain biochemical parameters characteristic of renal injury and its in vivo metabolism by quantitating the TRI principal urinary metabolites. Treatment of rats with TRI up to 11 mmol/kg did not influence any of the measured biochemical parameters of nephrotoxicity. On the other hand, significant increases in the urinary level of N-acetyl-beta-glucose-D-aminidase (NAG) and glucose as well as serum urea nitrogen were observed at 24 h only at the highest dose level (22 mmol/kg) or TRI. Urinary excretions of both trichloroethanol and trichloroacetic acid reached an apparent saturation at the highest dose level of TRI. In inhalation studies, urinary levels of gamma-glutamyltranspeptidase, NAG, glucose, proteins, and serum urea nitrogen were significantly increased at 24 h when rats were exposed to either 1000 or 2000 ppm TRI for 6 h. The capacity of renal cortical slices to accumulate p-aminohippurate was significantly reduced 24 h after the exposure to 22 mmol TRI/kg (ip), or to 1000 or 2000 ppm TRI. These results have demonstrated that TRI exerts its acute nephrotoxic potential at a very high dose level and produces nephrotoxic insult at the proximal tubular and possibly glomerular regions of the rat kidney, whether exposed by inhalation or by an ip route. These data further indicate an involvement of a capacity-limited metabolism in the expression of acute nephrotoxicity due to TRI in Fischer 344 rats.     

Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats receiving i.p. (mean +/- S.D.) (2.28 +/- 0.72 per cent) and i.v. (2.08 +/- 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p less than 0.01) and cardiac muscle (r = -0.82; p less than 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.     

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.     

Effects of inhaled 1,1,1-trichloroethane on the regional brain cyclic GMP levels in mice and rats

As it is known that volatile organic compounds (VOCs) exhibit differential dispositions among anatomically discrete brain regions in rodents as well as in humans, potential toxicological consequences of this pharmacokinetic feature were evaluated using measurements of cyclic GMP (glucose monophosphate). With the knowledge of 1, 1, 1-trichloroethane (TRI) uptake and distribution in the various brain regions, cyclic GMP was evaluated due to (1) known susceptibility to the effects of organic solvents, (2) pivotal physiological role in perpetuating changes in neurochemical pathways, and (3) possible involvement with neurobehavioral functions, whose disruption is one of the primary health effects associated with solvent exposures. Male CD-1 mice and Sprague-Dawley rats inhaled 5000 ppm TRI for 40 and 100 min in dynamic inhalation exposure chambers, and the brain was procured from the animals immediately following termination by microwave irradiation. After 40 min of TRI inhalation, significant decreases in cyclic GMP levels were found in the cerebellum of both species, 55% and 58%, respectively, relative to the controls. There was a further decrease in both species after 100 min of TRI inhalation. Smaller decreases in cyclic GMP were seen in the cortex of both species at both time points of measurement. A decrease in cyclic GMP was observed in the medulla oblongata of mice but not in rats after 40 min of exposure. Due to its signal transduction functions, it might be expected that the effects of TRI on cyclic GMP levels could directly impact neurological function. Comparison of the results from this study with the regional brain distribution of TRI and its effects on behavioral performance seen in previous studies by this laboratory appeared to indicate that alterations in brain cyclic GMP levels are only involved with the neurobehavioral toxicity of TRI in an indirect fashion; consequently, behavioral effects and decreases in cyclic GMP do not appear to be directly related to regionally differential dispositions of TRI in rodent brain.     

Pharmacokinetics of cefoxitin in patients with normal or impaired renal function

The pharmacokinetics of cefoxitin have been determined after a single i.v. injection of 15 mg/kg body weight in 10 patients with normal renal function and 20 patients with varying degrees of renal impairment. The kinetics of the antibiotic followed an open two-compartment model. In patients with normal renal function the following pharmacokinetic parameters were found: alpha = 8.66 h-1 beta = 1.21 h-1 K12 = 3.47 h-1 K21 = 3.17 h-1 K13 = 3.15 h-1 Vc = 4.24 l. Vp = 4.87 l. Vdss = 9.11 l. In the patients with renal impairment there was a significant decrease in alpha, beta, K12, K21 and K13, and an increase in the apparent volume of distribution. The degree of plasma protein binding in patients with normal renal function was 73.6% and this was diminished in patients with renal impairment. A linear relationship between K13 of cefoxitin and creatinine clearance was demonstrated. The dosage regimen for patients with renal impairment should be adjusted by modifying the dosage interval whilst maintaining the amount administered.     

Morphohistochemical characterization of suramin--induced chronic toxicity in rat kidney.

The effects of a chronic administration of suramin were evaluated on renal parenchyma of young rats. Animals were given suramin 18 mg/kg i.p. twice a week for two months, a treatment schedule equivalent to that used in cancer patients. At the end of the treatment, suramin concentrations in plasma and kidney were assayed and a morphohistochemical examination of renal parenchyma was carried out. Marked and widespread alterations were detected in both cortex and medulla and were associated with elevated tissue suramin levels exceeding 5 mg/g of tissue. The present data demonstrate that suramin induces a severe chronic renal damage in the rat, associated with high drug tissue levels.     

Increasing the selectivity of amikacin in rat peritoneal macrophages using carrier erythrocytes

The selectivity of amikacin in macrophages in vitro and its biodistribution in peritoneal macrophages and other tissues were studied in rats using carrier erythrocytes. Amikacin-loaded erythrocytes were prepared using a hypotonic dialysis method. The in vitro uptake of amikacin by peritoneal macrophages was studied using cell monolayers. The in vivo uptake by macrophages and the tissue distribution of amikacin were studied in two groups of rats that received either amikacin in saline solution, or amikacin-loaded erythrocytes. Pharmacokinetic analyses were performed using model-independent methods. The administration of the antibiotic using carrier erythrocytes elicited a higher accumulation in macrophages, both in vitro and in vivo. The tissue pharmacokinetics of amikacin in vivo using carrier erythrocytes revealed an accumulation of the antibiotic in specific tissues such as the liver and spleen. Minor changes in the pharmacokinetics were observed in organs and tissues such as renal cortex and medulla. According to the partition coefficients obtained, the relative uptake of amikacin when carrier erythrocytes were used was: spleen > peritoneal macrophages > liver > lung > renal cortex > renal medulla. Loaded erythrocytes can be seen to be potentially useful for the delivery of aminoglycoside antibiotics in macrophages.     

Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics.

Trichloroethylene (TRI) is readily absorbed into the body through the lungs and gastrointestinal mucosa. Exposure to TRI can occur from contamination of air, water, and food; and this contamination may be sufficient to produce adverse effects in the exposed populations. Elimination of TRI involves two major processes: pulmonary excretion of unchanged TRI and relatively rapid hepatic biotransformation to urinary metabolites. The principal site of metabolism of TRI is the liver, but the lung and possibly other tissues also metabolize TRI, and dichlorovinyl-cysteine (DCVC) is formed in the kidney. Humans appear to metabolize TRI extensively. Both rats and mice also have a considerable capacity to metabolize TRI, and the maximal capacities of the rat versus the mouse appear to be more closely related to relative body surface areas than to body weights. Metabolism is almost linearly related to dose at lower doses, becoming dose dependent at higher doses, and is probably best described overall by Michaelis-Menten kinetics. Major end metabolites are trichloroethanol (TCE), trichloroethanol-glucuronide, and trichloroacetic acid (TCA). Metabolism also produces several possibly reactive intermediate metabolites, including chloral, TRI-epoxide, dichlorovinyl-cysteine (DCVC), dichloroacetyl chloride, dichloroacetic acid (DCA), and chloroform, which is further metabolized to phosgene that may covalently bind extensively to cellular lipids and proteins, and, to a much lesser degree, to DNA. The toxicities associated with TRI exposure are considered to reside in its reactive metabolites. The mutagenic and carcinogenic potential of TRI is also generally thought to be due to reactive intermediate biotransformation products rather than the parent molecule itself, although the biological mechanisms by which specific TRI metabolites exert their toxic activity observed in experimental animals and, in some cases, humans are not known. The binding intensity of TRI metabolites is greater in the liver than in the kidney. Comparative studies of biotransformation of TRI in rats and mice failed to detect any major species or strain differences in metabolism. Quantitative differences in metabolism across species probably result from differences in metabolic rate and enterohepatic recirculation of metabolites. Aging rats have less capacity for microsomal metabolism, as reflected by covalent binding of TRI, than either adult or young rats. This is likely to be the same in other species, including humans. The experimental evidence is consistent with the metabolic pathways for TRI being qualitatively similar in mice, rats, and humans. The formation of the major metabolites--TCE, TCE-glucuronide, and TCA--may be explained by the production of chloral as an intermediate after the initial oxidation of TRI to TRI-epoxide.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiologically based pharmacokinetic model for cefazolin in rabbits and its preliminary extrapolation to man

In the present study, the physiologically based pharmacokinetic model, which succeeded previously in predicting the pharmacokinetics of beta-lactam antibiotics in rats [A. Tsuji, T. Yoshikawa, K. Nishide, H. Minami, M. Kimura, E. Nakashima, T. Terasaki, E. Miyamoto, C.H. Nightingale, and T. Yamana: Physiologically based pharmacokinetic model for beta-lactam antibiotics. I: tissue distribution and elimination in rats. J. Pharm. Sci. 72, 1239-1252 (1983)], was applied to cefazolin pharmacokinetics in rabbits and man. After iv bolus dosing in normal rabbits, the time courses of cefazolin concentration in plasma and various tissues (lung, heart, muscle, skin, bone, gut, liver, and kidney) were found to be very similar to those in rats. The values of physiological parameters (tissue plasma flows, tissue volumes, tissue/plasma albumin ratio) and biochemical parameters determined in this study (for nonlinear plasma protein binding, intrinsic renal clearance of active secretion and reabsorption) were incorporated into mass balance equations derived from the model. There was reasonable agreement between the model predictions and the observed data for cefazolin and inulin in rabbits. The model was also successful in the prediction of cefazolin disposition in rabbits with renal failure. Using available information reported for cefazolin in man, a preliminary extrapolation from the present model was attempted, and the overall predicted results after iv administration of 1 g cefazolin in man were compared with the serum and bone tissue data. The length of the effective antibacterial period for the drug is also discussed in terms of its predicted concentration unbound with proteins in various tissue interstitial fluids in man.     

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.