Tissue distribution studies

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

S3B Pharmacokinetics Guidance for Repeated Dose Tissue Distribution Studies Toxicity Testing... 

There were no effects at any of the doses tested on the histopathology of the brain for any duration or route of exposure (Gorzinski et al. 1985 NTP 1977, 1989 Weeks et al. 1979). This observation is consistent with tissue distribution studies which indicate that hexachloroethane has no particular affinity for the brain tissues (Fowler 1969b). 

Exposure Assessment. Single and multiple dose pharmacokinetics, toxicokinetics and tissue distribution studies in relevant species are useful. Proteins are not given orally demonstrating absorption and mass balance is not typically a primary consideration. Rather, this segment of the test should be designed to determine... 

S3B Pharmacokinetics Guidance for repeated dose tissue distribution studies Oct 94... 

As some of the toxicity observed with DPP-8/9 inhibitors 4 and 7 in predinical species suggested a potential immune system role, we hypothesized that the immunological effects observed with historical DPP-4 inhibitors [14] might be due to inhibition of DPP-8/9 instead of DPP-4 as initially reported. Sure enough, when these historical compounds were assayed at DPP-8/9 and DPP-4, they possessed more potent intrinsic inhibition at DPP-8/9 than at DPP-4 [20]. Furthermore, we demonstrated that DPP-8/9 inhibitor 7 is able to attenuate proliferation and IL-2 release in human in vitro models of T-cell activation, while a selective DPP-4 inhibitor does not. Recent tissue distribution studies also suggest a role for DPP-8 in the immune system [25]. 

Khera KS, Villeneuve DC, Terry G, et al. 1976. Mirex A teratogenicity, dominant lethal and tissue distribution study in rats. Food Cosmet Toxicol 14 25-29. 

Villeneuve DC, Khera KS, Trivett G, et al. 1979a. Photomirex A teratogenicity and tissue distribution study in the rabbit. J Environ Sci Health [B] 14(2) 171-180. 

The partition coefficients of these compounds ranged from 25 (bis-methyl diatrizoate) to 10 ° (derivative of 2 with a C18 chain length of the carboxylic acid). Tissue distribution studies in mice showed good liver uptake of these substances, particularly for those with intermediate chain lengths. No human data have been reported so far. 

Distribution, including accumulation of an absorbed substance, will be the same irrespective of the route of administration. However, distribution and accumulation at the site of apphcation (inhalation, oral, dermal) may depend on the route of administration. In such cases, local accumulation may occur and may be responsible for tissue damage. In these cases, systemic toxicokinetics of the substance may be of limited relevance for the risk assessment. It is generally not cmcial for risk assessment to determine the precise tissue distribution profile for a substance. In certain special cases, however, specific tissue distribution studies may assist or even be essential for the interpretation of available toxicological data. For example, it may be of interest to know whether the substance will cross the blood-brain barrier, the placenta barrier, or will accumulate in specific tissues. 

The tissue distribution study of these NCA[131I]-6-iodo-steroids in liver, spleen, adrenal, stomach, tyroid and lung showed a very rapid adrenal uptake with a peak value (in rats) at 15 min post-injection or at even shorter time periods363. 

Tissue distribution studies in mice revealed that, 48 h after 200 mg/kg oral administration of JM216, platinum levels were the highest in the liver (6-19 pg Pt/g tissue) and kidney (2.8-12 pg Pt/g tissue). This is 5 times higher than that which has been reported after equivalent doses of cisplatin. All other tissues (spleen, heart, lung) had levels <3.1 pg Pt/g tissue. In the liver a time course of platinum levels showed that the Cmax were reached by 2 hpost administration [22], Following administration of 200 mg/kg JM216 orally (in oil or in saline) 8% of platinum was eliminated in urine over 72 h and 66% was present in the faeces after 72 h. 

ICH S3B. Pharmacokinetics Guidance for Repeated Dose Tissue Distribution Studies. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, 27 October 1994. 

Distribution studies with radiolabeled test substances in animals are an important part of the drag development process. Traditional routine methods used for these studies are quantitative tissue distribution studies (QTD) and alternatively whole-body autoradiography (WBA) with detection of the radioactivity in whole-body sections on X-ray film (John R. J. Baker 1989). WBA is a qualitative detection method with a very high local resolution which includes all organs an many small substructures. 

To save animals and time, the quantitative tissue distribution study is more and more replaced by the quantitative whole-body autoradiography. 

Some researchers think that WBA should replace the classic tissue distribution study to profile the organs and systems that are exposed and may accumulate the drug candidate and its metabolites. 

Tissue distribution studies were also done in rats after nasal administration. As seen in Figure 14 and Table 2, it was found that the elimination half-life of the unmodified sCT was 199 min, whereas the SP-mPEG2000-modified sCT showed an increased terminal elimination with a half-life of 923 min. It was also found that the SP-mPEG2000-modified sCT took a significantly longer time to reach its maximum concentration, 520 min, as compared with the 77 min for the unmodified sCT, and the AUC was found to be 20,638 pg/min/mL, which is much higher than the 3650 pg/ min/mL for the unmodified sCT. The authors reported that the increase in the terminal half-life observed could be due to a flip-flop phenomenon. Also, when the tissue distribution of the formulation was examined 12 h after administration, the highest radioactivity was found in the liver. The details of the biodistribution studies are as shown in Table 3. 

To clarify the purity, labeling site, specific radioactivity, stability, the guidance on repeated dose tissue distribution studies is to be referred in the Notification No. 442 of the PAB in July 1996. 

Once absorbed, butadiene is rapidly distributed throughout the body. A tissue distribution study in rats indicates that the highest concentrations of butadiene are located in peripheral fat lower concentrations are observed in the liver, brain, spleen, and kidney. 

In laboratory animals, no anticholinergic, al-ad-renergic, or )S-adrenergic-receptor blocking effects were observed. No sedative or other central nervous system effects were observed. Radiolabeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood-brain barrier. 

Heptanone is absorbed into the bloodstream after ingestion, inhalation, or dermal exposure. Results of tissue distribution studies of " C-methyl -amyl ketone in rats comparing intraperitoneal and inhalation... 

To evaluate the distribution and metabolism of [3H] tafluprost in ocular tissues and to study the IOP-lowering effects of the major metabolites of tafluprost, single ocular doses of [3H]tafluprost were administered to male/female cynomolgus monkeys (1 pg/eye for tissue distribution studies and 10 pg/eye for metabolic studies) [46]. Tafluprost was rapidly absorbed into ocular tissues and subsequently entered the systemic circulation. The highest concentrations of radioactivity were observed in the bulbar conjunctiva and the palpebral conjunctiva (323 and 180ng-eq/g, respectively) at 0.083 h after administration, and in the cornea (784ng-eq/g) at 0.25 h after administration. Nonvolatile radioactivity in plasma peaked (0.907 ng-eq/g) at 0.083 h after administration and then declined steadily. Three major metabolites shown in Figure 2.7, a carboxylic acid of tafluprost (AFP-172), 1,2-... 

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