Carrier-mediated uptake of grepafloxacin, a fluoroquinolone antibiotic, by the isolated rat lung cells

Grepafloxacin (GPFX) is a new quinolone antibiotic (NQ) which is highly distributed to the lung and other tissues. In the present study, to characterize the distribution mechanism of GPFX to the lung, the uptake of GPFX by isolated rat lung cells was examined in vitro. GPFX was rapidly taken up by the cells, and the uptake reached a steady-state within 5 min. The cell-to-medium concentration ratio at equilibrium was 56.8+/-1.9 microL/mg protein, which was much higher than the cellular volume. GPFX uptake consisted of a saturable component (Km: 264+/-181 microM, Vmax: 2.94+/-2.33 nmol/min/mg protein) and a nonsaturable component (Pdif: 7.04+/-2.17 microL/min/mg protein). The uptake of GPFX was reduced in the presence of ATP-depletors (FCCP and Rotenone) and by the replacement of sodium with choline in the medium, suggesting that GPFX uptake is at least partially mediated by an Na+- and energy-dependent process. GPFX uptake tended to be reduced in the presence of other NQs such as levofloxacin, lomefloxacin and sparfloxacin, but was only minimally affected by the substrates of several uptake mechanisms already identified in the liver and kidney such as taurocholate, p-aminohippurate, L-carnitine and tetraethylammonium. These results suggested that GPFX is taken up by the lung partially via carrier-mediated transport system(s), distinct from the identified transporters, and such active transport systems may at least partially account for the efficient distribution of GPFX to the lung.     

Enantioselective Tissue Distribution of the Basic Drugs Disopyramide, Flecainide and Verapamil in Rats: Role of Plasma Protein and Tissue Phosphatidylserine Binding

Purpose. The stereoselective distribution of three basic drugs, disopyramide (DP), flecainide (FLC) and verapamil (VP), was studied to clarify the relationships between the tissue-to-unbound plasma concentration ratio (Kpf) and drug lipophilicity and binding to phosphatidylserine (PhS), which are possible factors determining the tissue distribution of these drug enantiomers. Methods. The drug enantiomer or racemate was administered to rats by intravenous constant infusion. Their concentrations in plasma and tissues were determined using enantioselective high-performance liquid chromatography. Plasma protein binding, and buffer-octanol and buffer-hexane containing PhS partition coefficients were also determined. Results. The stereoselectivity of the tissue-to-plasma concentration ratio (Kp) was partly associated with that of serum protein binding. However, the Kpf value of R( + )-VP in the lung was significantly higher than that of S(–)-VP. A linear correlation was observed between the Kpf values of these drug enantiomers in brain, heart, lung and muscle, and their buffer-hexane containing PhS partition coefficients. The in vitrodata for the binding of these drugs to PhS suggest that stereoselective binding of VP to PhS may correspond to its stereoselective tissue binding. Conclusions. Our findings provide some evidence for a role of tissue PhS in the tissue distribution of basic drugs with respect to stereoselectivity of drug enantiomers distribution.     

Differences in the hepatobiliary transport of two quinolone antibiotics, grepafloxacin and lomefloxacin, in the rat

The biliary excretion of grepafloxacin (GPFX) was compared with that of lomefloxacin (LFLX) in rats. The biliary clearances (Cl(plasma)(bile)) of GPFX was 2.9 times greater than LFLX based on the plasma concentration reached during constant intravenous (i.v.) infusion. The liver-plasma unbound concentration ratio, K(pu), of GPFX (1.7) was also higher than that of LFLX (0.7). The hepatic uptake clearance, assessed from an integration plot analysis, of GPFX was comparable with the hepatic blood flow rate, and 1.5 times that of LFLX, indicating that membrane transport in the uptake process is more efficient for GPFX. This was also supported by the difference between the uptake clearance of GPFX and LFLX in isolated rat hepatocytes. The bile-liver unbound concentration ratio of GPFX and LFLX was approximately 6 and 3, respectively, and the biliary clearance based on the unbound liver concentration of GPFX was 1.8 times that of LFLX. These results suggest that the concentrative transport of GPFX also across the canalicular membrane was more efficient than that of LFLX. Thus, the membrane transport activity via both sinusoidal and canalicular membranes determines the net excretion of each compound.     

Physiologically-based pharmacokinetic analysis of grepafloxacin

Grepafloxacin (GPFX) is a synthetic new quinolone antimicrobial agent that possesses an extensive tissue distribution and exhibits a strong antibacterial activity in vivo. In this study, the tissue distribution characteristics of GPFX were examined using tissue concentration-time profiles following intravenous administration to rats. Subsequently, the pharmacokinetics of GPFX were analyzed based on the physiological pharmacokinetic model. The tissue-to-plasma partition coefficients (Kp) of GPFX in rats were high in all tissues except brain. A pharmacokinetic model for rabbits, monkeys and dogs was constructed using the tissue-to-plasma free concentration ratio (Kp,f) of GPFX in rats to simulate the GPFX concentration-time profile in plasma following intravenous administration of GPFX to each animal. The calculation-derived concentrations correlated well with the experimentally-derived data, suggesting that there are no interspecies differences in the high tissue distribution characteristics of GPFX. The clearance rates of GPFX in humans were predicted from the pharmacokinetic parameters of rats, rabbits, monkeys and dogs by an animal scale-up method and a pharmacokinetic model for humans was constructed. The GPFX concentration-time profiles in plasma, following oral administration of GPFX to humans, were predicted within 0.5-1.0 h of mean absorption time and the calculation-derived results were in good agreement with the experimental data. Thus, it is suggested that the concentration-time profile in plasma and all human organs can be predicted from the pharmacokinetic data of animals.     

Lung tissue distribution after intravenous administration of grepafloxacin: comparative study with levofloxacin

The aim of the present study is to study the pharmacokinetics in plasma, lung lymph and bronchial washing fluid after intravenous infusion of grepafloxacin (GPFX), in comparison with those of levofloxacin (LVFX). Four conscious sheep with chronically instrumented lung lymph fistulas and tracheotomy were prepared. GPFX and LVFX concentrations in plasma and lung lymph after intravenous infusion of the drugs (10 mg/kg) for over 10 min were measured. In addition serial bronchial washing with 50 mL normal saline was performed to obtain epithelial lining fluid (ELF) at 2, 4, 6, 8, 12, 24 h after the intravenous administration. The time courses of lung lymph concentration were almost identical to those of the concomitant levels of both GPFX and LVFX in plasma, suggesting that both GPFX and LVFX could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. However, GPFX concentrations of ELF were significantly higher than LVFX concentrations over time after the administration. In addition, intracellular concentrations in ELF of GPFX were also extremely high compared with those of LVFX. These results demonstrated that penetration of GPFX in bronchial wall, bronchial epithelium and/or phagocytic cells was superior to that of LVFX. These observations suggest that the pharmacokinetic characteristics of GPFX in the lung may provide a new insight into the strategy for clinical treatment of various pulmonary infections, especially cytotropic bacterial infections.     

Determination of lipophilicity of two quinolone antibacterials, ciprofloxacin and grepafloxacin, in the protonation equilibrium.

The objective of this study was to compare protonation equilibrium and lipophilicity of two quinolone antibacterials, grepafloxacin (GPFX) and ciprofloxacin (CPFX), in order to give an insight into effects on the physicochemical properties by slight structural motifs. The protonation equilibrium was investigated by a spectrophotometry. Macro- and micro-dissociation constants were simultaneously determined, based on nonlinear regression analysis using the MULTI program, and then microspecies distribution could be described accordingly. Zwitterionic microspecies predominated at isoelectrical point (pI) for both drugs, and the concentration ratio of neutral to zwitterionic forms was near 4-fold greater for GPFX than that for CPFX. The apparent partition coefficient (D(O/B,pH)) versus pH profiles had the shape of a parabolic curve in an n-octanol/buffer system, and reached the maximum around pI for both, respectively. Moreover, two introduced methyl groups in GPFX increased not only intrinsic lipophilicity but also neutral microspecies fraction relative to CPFX, and D(O/B,pH) of GPFX was consequently far higher than that of CPFX. The results emphasized that there were significant differences in protonation equilibrium and lipophilicity between GPFX and CPFX, which conduced to explaining their different behavior in terms of antibacterial activities and pharmacokinetics.     

Phosphatidylserine as a Determinant for the Tissue Distribution of Weakly Basic Drugs in Rats

Interorgan variation in tissue distribution of weakly basic drugs such as quinidine, propranolol, and imipramine was investigated as a function of binding to phosphatidylserine (PhS) in tissues. Tissue distributions of these drugs were determined using 10 different tissues at a steady-state plasma concentration and were expressed as tissue-to-plasma partition coefficients (K _p values). The concentration of PhS in the tissue was determined by two-dimensional thin-layer chromatography. Plotting of K _p values, except for brain, against the tissue PhS concentrations showed a linear relationship, indicating that PhS is a determinant in the interorgan variation of these tissue distributions. Further, differences in tissue distribution among the drugs was considered to be due to the difference in binding potency to PhS. Drug binding parameters to individual standard phospholipid were determined using a hexane-pH 4.0 buffer partition system. Binding was highest to PhS, and a linear relationship was found between the log nK [product of the number of binding sites (n) and the association constant (K) for PhS binding] obtained in vitro and K _p values of drugs in tissues in vivo. The empirically derived equation, K _p = 14.3 × (log nK) × (PhS cone.) – 8.09, was found to predict K _p values in vivo of weakly basic drugs. Thus, a determinant of interorgan variation in the tissue distribution of the weakly basic drugs studied was the tissue concentration of PhS and the drug binding affinity to PhS.     

Distribution characteristics of grepafloxacin, a fluoroquinolone antibiotic, in lung epithelial lining fluid and alveolar macrophage

The purpose of this study was to investigate the distribution of Grepafloxacin (GPFX), a new quinolone antimicrobial agent, in the lung epithelial lining fluid (ELF) and the alveolar macrophage (AM) in rats, which are potential infection sites in respiratory tract infections. We also aimed to clarify the mechanism governing the transferability of GPFX into the alveolus compartment from a kinetic point of view. The AUC ratios of ELF/plasma and AM/plasma after the oral administration of GPFX were 5.69 +/- 1.00 and 352 +/- 57, respectively, which were several-fold greater than those of ciprofloxacin (CPFX). Pharmacokinetic analyses of time profiles of GPFX concentrations in ELF and AM revealed that the influx clearance from plasma to ELF across the alveolar barrier is 5-fold greater than the efflux clearance from ELF. In addition, the permeability of GPFX across the cultured AM cell membrane was 7-fold and 11-fold greater than that of levofloxacin (LVFX) and CPFX, respectively. The extent of intracellular binding to AM cells (expressed as a constant (alpha)) was the greatest for GPFX, followed by CPFX and LVFX. There was a significant correlation between the alpha value and the partitioning to the immobilized artificial membrane (IAM) column, which consists of phospholipid residues covalently bound to silica. These results suggest that GPFX is highly distributed in ELF and AM, and that the high transferability of GPFX into ELF may be attributable to the existence of asymmetrical transport across the alveolar barrier. In addition, it was suggested that both rapid permeability across the AM cell membrane and avid binding to the membrane phospholipids may be responsible for the high accumulation of GPFX in AM.     

Allylamine cardiovascular toxicity: V. Tissue distribution and toxicokinetics after oral administration

We studied the uptake, tissue distribution, toxicokinetics, and excretion of allylamine by giving rats [14C]allylamine (1.5 microCi/kg; 150 mg/kg) by gavage. Rats were killed at intervals up to 2 h, and multiple tissues were sampled. Aorta showed the highest counts of 14C-label at most times (5-10-fold higher than most other organs, 100-fold higher than blood), although a minority of aortas had very low counts. Coronary arteries dissected from the hearts showed consistently higher 14C-label than myocardium. Liver counts, which were high at 5 min, decreased rapidly; kidney counts slowly increased until 45 min, then decreased rapidly, consistent with an excretory function for this organ. Counts of 14C-label were lower in all other organs, including lung, skeletal muscle, brain, testes, pancreas, adrenal, spleen, fat, and blood. Toxicokinetic study showed a very rapid absorption rate and short half-lives (less than 1 h) for those organs which reasonably fit a toxicokinetic one-compartment model. 14C-label was rapidly excreted in the urine; approximately 60% of the dose given was recovered by 24 h. No counts were found in feces. These studies indicate that allylamine--or its metabolite(s)--has a unique predilection for elastic and muscular arteries, such as aorta and coronary arteries. This relatively specific cardiovascular toxin acts as a highly polar, highly water soluble substance, which is rapidly absorbed from the gastrointestinal tract, has a short half-life in most tissues, and is rapidly excreted in the urine. The actual mechanisms by which allylamine injures tissue, especially in view of its rapid sequestration in vascular tissue, remain to be uncovered.     

Comparison of intravenous ibuterol (KWD 2058), a new bronchodilator,and terbutaline

Summary The selectivity of the recently developed -stimulating drug ibuterol, a terbutaline ester which is rapidly hydrolyzed to terbutaline in vivo, was tested by comparing it with terbutaline after intravenous infusion. Dose-response curves for both drugs for FEV*₁, heart rate, blood pressure, and tremor were recorded. The two drugs had equal bronchodilator effect. Ibuterol caused significantly less increase in heart rate, tremor ratio, and pulse amplitude when doses causing equal bronchodilation were infused. This is probably due to inequality of distribution. The lower tremorogenic activity of ibuterol can also be caused by differences in the concentration of tissue esterases in lung and skeletal muscle. It is concluded that ibuterol is more selective for the bronchi than terbutaline.     

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)     

Effect of amiodarone on phospholipid content and composition in heart, lung, kidney and skeletal muscle: relationship to alteration of thyroid function

To investigate the effect of chronic amiodarone treatment on tissue phospholipids, a marker of amiodarone-induced toxicity, and to test the hypothesis that tissue phospholipids changes are related to amiodarone-induced effects on thyroid function, male Wistar rats were treated with amiodarone and tissue phospholipid content and fractions were assessed. Twenty-six animals were allocated to 4 groups: (i) group 1 received amiodarone, 20 mg/kg per day, for 3 weeks (n = 6); (ii) group 2 received amiodarone for 5 weeks (n = 6); (iii) group 3 received drug for 6 weeks (n = 6), and (iv) group 4 (control group) received the diluent for 6 weeks (n = 8). Total phospholipid content of lung, kidney and skeletal muscle but not heart was increased after 3 weeks of amiodarone treatment. With longer durations of treatment, the phospholipid content was significantly (p < 0.05) reduced in all four organs. The proportion of phospholipids in different classes was modified by amiodarone treatment with the most consistent changes across different tissues being reductions in phosphatidylethanolamine and increases in phosphatidylserine. Serum thyroxine concentration was significantly (p < 0.05) reduced at 5 weeks of treatment and thereafter. There was a significant correlation between serum thyroxine and total phospholipid concentration in heart (r = 0.555; p < 0.05) and lung (r = 0.502; p < 0.05). For heart, there was a significant correlation between serum thyroxine and the distribution of phospholipid classes, mainly for phosphatidylserine even after considering amiodarone dose. The same was found in the lung. In the kidney and skeletal muscle, there was a significant (p < 0.05) correlation between serum thyroxine and the proportion of phospholipids in phosphatidylcholine and sphingomyelin. In conclusion, this study presents the novel finding of a biphasic tissue phospholipid response to amiodarone characterized by a short term increase in phospholipids in lung, kidney and skeletal muscle but not the heart followed by a long term decline in phospholipids in all four organs that is likely due to a direct action of amiodarone on phospholipid metabolism and potentially the result of amiodarone-induced reduction in thyroid function.     

Influence of Ammonium Chloride on the Tissue Distribution of Anticholinergic Drugs in Rats

Ammonium chloride (NH₄***C1) increases lysosomal pH and thereby abolishes intralysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated. The tissue-plasma concentration ratios (K_p) of these drugs in various tissues were determined by infusion studies at steady-state in the presence or absence of NH₄***C1. Treatment with NH₄***C1 reduced the K_p values for both drugs, causing the largest reduction in K_p in the lung (52.1 to 11.8 for biperiden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68, respectively), followed by the heart and kidneys, with relatively small reductions in the brain, gut, muscle and fat. Subcellular fractionation studies in the lung indicated that the subcellular fraction-plasma concentration ratio of each drug at the steady state (K_p,sf) was reduced by treatment with NH₄***C1, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlation was found between the ratio of decrease in K_p,sf after NH₄***Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945). These results suggest that acidic organelles contribute significantly to the distribution kinetics of anticholinergic drugs.     

Studies on the mechanism of subcellular distribution of basic drugs based on their lipophilicity

This paper described the studies on the mechanism of subcellular distribution of lipophilic weak bases. Although the tissue distribution of basic drugs appeared to decrease with time simply in parallel with their plasma concentration, their subcellular distribution in various tissues exhibited a variety of patterns. Basic drugs were distributed widely in various tissues, but were concentrated in lung granule fraction, where their accumulation was dependent on their lipophilicity and lysosomal uptake. As the plasma concentration of drugs decreased after maximum level, the contribution of lysosomes to their subcellular distribution increased. The uptake of the basic drugs into lysosomes depended both on their intralysosomal pH and on the drug lipophilicity. As the lipophilicity of the basic drugs increased, they accumulated more than the values predicted from the pH-partition theory and raised the intralysosomal pH more potently, probably owing to their binding with lysosomal membranes with or without additional intralysosomal aggregation. These phenomena should be considered as a basis of drug interaction in clinical treatments.     

Pharmacokinetics and biodisposition of fluorescein-labeled arabinogalactan in rats

Fluorescein-labeled arabinogalactan (FA) was prepared by the reaction with FITC in methyl sulphoxide according to the method of deBelder and Granath. A systemic kinetic analysis of FA in rats was carried out by using a specific high-performance size-exclusion chromatography. Intravenously administered FA was rapidly eliminated from the blood circulation followed by an appreciable distribution to the liver and kidney. FA was accumulated in these organs over a long period whereas negligible levels of FA were detected in the other organs. A marked dose-dependency was seen in the hepatic uptake of FA which was markedly reduced by coinjected asialofetuin whereas the renal uptake of FA was not altered. Measurement of the hepatocellular localization demonstrated the overwhelming distribution of FA in the parenchymal liver cell fraction. Furthermore, the microscopic examination revealed FA that was effectively endocytosed by the parenchymal liver cells. These results suggested that FA which is bound to the asialoglycoprotein receptor with a high affinity is subsequently internalized to the hepatocyte via receptor-mediated endocytosis. FA was partially activated by periodate oxidation in order to acquire aldehyde groups to which guest molecules can be bound. A 12.5% oxidized arabinogalactan keeping a hepatocellular targetability showed a good conjugating reactivity to guest molecules via Schiff-base formation or by reductive amination. It was suggested that arabinogalactan can serve as a potential carrier for the delivery of enzymes and drugs to the parenchymal liver cells via the asialoglycoprotein receptor.     

Tissue distribution of 14C-diazepam and its metabolites in rats

We have kinetically investigated the tissue distribution of 14C-diazepam and described the appearance and disappearance of its metabolites (3-hydroxydiazepam, desmethyldiazepam, and oxazepam) following a single iv injection of 14C-diazepam into rats. Significant amounts of oxazepam were detected in plasma and various tissues in the rat, contrary to previous reports. Concentration-time profiles of diazepam in the main disposing organs (liver, kidney, and lung) and the other organs (brain, heart, and small intestine) indicated that diazepam was distributed rapidly to these organs. Concentration-time profiles of diazepam in the main tissues for drug distribution (skin and adipose) indicated that diazepam was slowly distributed to these tissues, whereas that in muscle, which is also responsible for drug distribution, indicated that diazepam was less rapidly distributed to this tissue. Metabolites appeared in plasma and various tissues or organs immediately after iv injection of diazepam. Metabolites levels in plasma and various tissues or organs were significantly lower than that of diazepam except for liver and small intestine, where metabolites levels were higher compared to that of diazepam and metabolites exhibited a considerable persistence.     

Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat

The purpose of this research was to identify the major factors controlling the distribution of beta-blockers (acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol, propranolol and timolol) in rats, across tissues, compounds and enantiomers. Tissue distribution was assessed at steady state by infusing cassette doses of beta-blockers into the jugular vein via an indwelling catheter at a constant rate. Blood was sampled via an indwelling catheter in the carotid artery, and 12 tissues excised at the end of dose infusion (4 or 8 h). Drug concentrations were quantified using a novel chiral LC-MS method and the tissue-to-plasma (Kp) and tissue-to-plasma water (Kpu) values were calculated for each tissue. Differences between Kp were observed between many enantiomeric pairs, and largely explained by enantiomeric differences in plasma protein binding. Across compounds, Kpu values were generally highest in lung and lowest in adipose, and were higher for the more lipophilic drugs betaxolol and propranolol. For any tissue, Kpu differences between the individual beta-blockers correlated well with the corresponding affinity for blood cells. For all compounds, regional tissue distribution correlated well with tissue acidic phospholipid concentrations, with phosphatidylserine appearing to have the strongest influence. This information may be used as the basis for predicting the tissue distribution of basic drugs.     

Tissue penetration properties of macrolide antibiotics--comparative tissue distribution of erythromycin-stearate, clarithromycin, roxithromycin and azithromycin in rats]

The ability of antibiotics to penetrate the target organs is an important factor for the clinical effects and side effects in the treatment of infection. In the present study, the comparative tissue distribution of 4 kinds of macrolide antibiotics was determined in rats. After oral administration of 20 mg/kg, roxithromycin (RXM) had the highest plasma concentration, and clarithromycin (CAM) has the second highest. The Cmax of RXM and CAM were 2.7 and 1.0 micrograms/ml, respectively. On the other hand, both levels of erythromycin-stearate (EM-S) and azithromycin (AZM) were extremely low, with a Cmax of 0.1 microgram/ml. Concentration of the 4 compounds were measurable in the liver, kidney, spleen, lung and heart. The concentration in all tissues for each compound were significantly higher than those in the plasma. AZM had the most sustained and the highest tissue levels. The distribution patterns of RXM and AZM were almost similar to the case of EM-S, in that the highest tissue concentration was observed in the liver, followed in descending order by concentration in the kidney, spleen, lung and heart. On the other hand, CAM had the highest concentration in the lung, and was moderated in the liver. Major clinical indications are infections of the respiratory tracts, and commonly reported side-effects are hepatotoxity. Therefore, it is worth noting that the lung levels of CAM were significantly higher than in the liver, as the separation of clinical effects and side-effects.     

Tissue distribution studies of [18F]haloperidol, [18F]-beta-(4-fluorobenzoyl)propionic acid, and [82Br]bromperidol by external scintigraphy

Tissue distribution studies of [18F]haloperidol and [82Br]bromperidol, two potent neuroleptic drugs, were performed in rats by serial sacrifice. The usefulness of external scintigraphy in obtaining tissue distribution data in large animals is demonstrated by the tissue distribution of [18F]haloperidol in rhesus monkeys. Both serial sacrifice and external scintigraphic studies demonstrated that uptake of the two drugs after intravenous administration into their target organ, the brain, was very fast and that the ratio of brain to blood levels was high throughout the 2-hr observation. Bromperidol appeared to reach peak brain levels faster than its chloro analog, haloperidol. Both bromperidol and haloperidol concentrated overwhelmingly in the rat lung. Haloperidol also showed a high affinity for the monkey lung. The disposition pattern in rats of [18F]-beta-(4-fluorobenzoyl)propionic acid, an apparent intermediate in butyrophenone metabolism, was entirely different from that of the parent drugs. This metabolite did not concentrate in the rat brain.     

The Contribution of Lysosomal Trapping in the Uptake of Desipramine and Chloroquine by Different Tissues

Abstract: Cationic amphiphilic drugs strongly accumulate in tissues of different organs. Uptake is controlled by two major mechanisms, non-specific binding to membrane phospholipids, and ion-trapping within acidic cellular compartments. The aim of this study was to assess the individual contributions of these two mechanisms on the uptake in vitro of desipramine and chloroquine into tissue slices of control and desipramine-treated rats. Drug uptake into intact slices was compared with uptake into slices with destroyed or non-functional acidic compartments. The sequence of desipramine uptake by tissue slices of eight different organs was: lungs>brain>heart>diaphragm>kidneys>skeletal muscles>adipose tissue>liver. The low desipramine concentration in liver may be due to metabolism of the parent drug by cytochrome P-450. Uptake of chloroquine differed widely between slices of different organs with the sequence: lungs>kidneys=brain=liver>diaphragm=heart=skeletal muscles>adipose tissue. Destruction or inactivation of the acidic compartments by homogenization and freeze-thawing or by ammonium chloride, sodium fluoride, or monensin, reduced drug uptake to similar extents. The reduction was organ-specific and may represent the size of the lysosomal compartment in the respective tissue cells. Uptake of chloroquine was more affected than that of desipramine, suggesting that ion-trapping is the main factor for chloroquine accumulation, while binding to membrane phospholipids, is the main factor for desipramine uptake. Single or multiple-dose treatments of rats with desipramine hardly had any effect on consecutive desipramine uptake into lung and liver slices, while the accumulation of chloroquine was enhanced in these slices. In conclusion, the extent of uptake of cationic amphiphilic drugs into tissue slices was tissue-specific, and the contribution of the two uptake mechanisms was strongly drug-dependent.