To obtain more insight in the relationship between physicochemical properties of cationic drugs and their hepatobiliary transport rate, a series of 12 aminosteroidal neuromuscular blocking agents (NMBAs), supplemented with data of four related NMBAs from the literature, were investigated in the isolated perfused rat liver. A significant correlation was found between plasma protein binding and the partition coefficient octanol/Krebs (log P), confirming results from the literature with other organic cations. Evidence was found for a saturable hepatic uptake of several NMBAs, indicating that carrier-mediated uptake processes are involved. Hepatic uptake rate was closely related to the lipophilicity of the compounds; the initial extraction ratio, the apparent clearance and the intrinsic clearance were significantly correlated to log P. We did not find a significant correlation between biliary clearance and lipophilicity in the current series of compounds. Pharmacokinetics analysis of perfusate disappearance and biliary excretion data revealed that a considerable fraction of the dose of these bulky organic cations is stored in the liver and seems to not be directly available for biliary excretion. This finding is in line with earlier observations showing a pronounced accumulation of this type of compounds in mitochondria and lysosomes.
The influence of photoacclimation on the effects of excessive photosynthetically active (PAR; 400-700 nm) and ultraviolet (UVR; 280-400 nm) radiation was assessed for the marine diatoms Thalassiosira weissflogii (Grunow) Fryxell and Hasle and Thalassiosira antarctica (Comber). Low and high PAR acclimated cultures were subjected to simulated surface irradiance (SSI) that mimicked irradiance around noon, including UVR. PSII efficiency, xanthophyll conversion, superoxide dismutase (SOD) activity, carbohydrate buildup, and lipid peroxidation were investigated after 30 min SSI and during 120 min recovery in low irradiance. Furthermore, viability loss was measured during 4 h SSI. Prior to SSI, the diadino-diatoxanthin pool was increased in high irradiance acclimated cells, compared with cells grown under low irradiance. Thirty-minutes SSI caused a pronounced decline in PSII efficiency. This coincided with de-epoxidation of diadinoxanthin in high irradiance acclimated cells, which was completely reversed during recovery in low irradiance. De-epoxidation was lower for low irradiance acclimated cells, whereas PSII efficiency and carbohydrate buildup were lower during the recovery phase. Furthermore, clear UVR effects on PSII efficiency were observed in low irradiance but not in high irradiance acclimated cells. Although 30 min SSI did not increase cellular SOD activity and lipid peroxidation, prolonged (4 h) SSI caused viability loss in low irradiance acclimated cells, which was enhanced by UVR. Therefore, PAR and UVR-induced PSII inactivation and viability loss were reduced by high irradiance-mediated changes in light harvesting and the xanthophyll pigments. In addition to photoacclimation-modulated differences, minor sensitivity differences were found between species.
Aim: Iohexol plasma clearance is used as an indicator of kidney function in clinical and preclinical settings. To investigate the pharmacokinetic profile of iohexol, a rapid, simple method for measurement of iohexol in different matrices and species was needed. Materials & methods: Iohexol was separated on an Accucore C18 column (Thermo Fisher Scientific, CA, USA). Detection was performed on a Thermo Scientific Quantiva tandem quadrupole mass spectrometer. The method was validated according to the requirements for bioanalytical methods issued by the US FDA and European Medicines Agency. Conclusion: We developed and validated a fast and efficient analytical method, suitable for analyzing iohexol in human EDTA plasma, human lithium-heparin plasma, human urine and goat- and pig EDTA plasma, using only one calibration line prepared in human EDTA plasma.
Prolonged elevation of plasma catecholamines is a risk factor for vascular diseases such as hypertension and atherosclerosis. Catecholamines induce hypertrophy of vascular smooth muscle through alpha1‐adrenoceptors (α 1 ‐ARs). In cell culture this involves the transactivation of epidermal growth factor receptor (EGFR). We hypothesized EGFR transactivation to be involved also in the α 1 ‐AR mediated aortic contraction. Thoracic aorta was isolated from 12‐14 weeks old male Wistar rats. In vitro aortic contractile responses to cumulative doses of phenylephrine (PE) were investigated in the absence and presence of EGFR antagonists AG1478 and DAPH in intact and endothelium‐denuded rings. Involvement of signal transduction pathways was investigated by using heparin and inhibitors of Src, MMP, ERK1/2 and IP3K. AG1478 concentration dependently decreased PE‐induced contractile responses in both intact (pA 2 =5,52) and denuded (pA 2 =5,47) rings, as did DAPH. In contrast, AG1478 did not affect contraction response to the thromboxane analog U46619. Blockade of IP3K by wortmannin abrogated the effect of AG1478 on the PE response, whereas heparin and inhibitors of Src, MMP and ERK1/2 did not affect the AG1478 action. α 1 ‐AR mediated contraction of aortic ring involves transactivation of EGFR, most likely via activation of the IP3K pathway and not by shedding of heparin‐binding EGF. This study was supported by GUIDE.
The effects of high PAR (400–700 nm), UVA (315–400 nm), and UVB (280–315 nm) radiation on viability and photosynthesis were investigated for Chaetoceros brevis Schütt. This Antarctic marine diatom was cultivated under low, medium, and high irradiance and nitrate, phosphate, silicate, and iron limitation before exposure to a simulated surface irradiance (SSI) treatment, with and without UVB radiation. Light‐harvesting and protective pigment composition and PSII parameters were determined before SSI exposure, whereas viability was measured by flow cytometry in combination with a viability stain after the treatment. Recovery of PSII efficiency was measured after 20 h in dim light in a separate experiment. In addition, low and high irradiance acclimated cells were exposed outdoors for 4 h to assess the effects of natural PAR, UVA, and UVB on viability. Low irradiance acclimated cells were particularly sensitive to photo induced viability loss, whereas no viability loss was found after acclimation to high irradiance. Furthermore, nutrient limitation reduced sensitivity to photo induced viability loss, relative to nutrient replete conditions. No additional viability loss was found after UVB exposure. Sunlight exposed cells showed no additional UVB effect on viability, whereas UVA and PAR significantly reduced the viability of low irradiance acclimated cells. Recovery of PSII function was nearly complete in cultures that survived the light treatments. Increased resistance to high irradiance coincided with an increased ratio between protective‐ and light‐harvesting pigments before the SSI treatment, demonstrating the importance of nonphotochemical quenching by diatoxanthin for survival of near‐surface irradiance. We conclude that a sudden transfer to high irradiance can be fatal for low irradiance acclimated C. brevis .
The time course of action of mivacurium does not correlate with its rapid breakdown by plasma cholinesterase. Pharmacokinetic-pharmacodynamic (PK-PD) modelling was applied to obtain more insight in the concentration-effect relationship.Fourteen patients between 25 and 55yr, undergoing non-major surgery, American Society of Anesthesiologists Grade I-II, were included. All patients received thiopentone/fentanyl/isoflurane/oxygen/nitrous oxide anaesthesia. Neuromuscular block was monitored mechanomyographically using single twitch stimulation (0.1 Hz). Mivacurium was administered as a short-term infusion, mean (standard deviation) duration 4.7 (1.0) min and dose 145 (33) microg kg(-1). Arterial blood samples were obtained, and plasma was analysed using high performance liquid chromatography. PK-PD modelling was performed using an iterative Bayesian two-stage approach, assuming that the trans-trans and cis-trans isomers are equally potent.A PK-PD model with an effect compartment linked to plasma did not fit to the data satisfactorily. A model using an interstitial space compartment between plasma and effect compartment fitted significantly better. Parameters (mean (percentage coefficient of variation)) of the best fitting model were: k(ip) 0.374 min(-1) (46%), k(ei) 0.151 min(-1) (36%), EC50 98 microg L(-1) (29%) and gamma 3.7 (22%).The PK-PD behaviour of mivacurium could be described using a model with an interstitial space compartment interposed between plasma and effect compartment. This model shows that the time course of mivacurium is mainly governed by the concentration decline in this interposed compartment and only indirectly related to the rapid plasma clearance.
In the present study it was tested whether known P‐glycoprotein (P‐gp) substrates/MDR reversal agents interact with small (type 1) and bulky (type 2) cationic drugs at the level of biliary excretion in the rat isolated perfused liver model (IPRL). The studies were performed with model compounds tri‐n‐butylmethylammonium (TBuMA) (a relatively small type 1 organic cation), rocuronium (Roc) (a bulky type 2 organic cation) and the classical P‐gp substrate doxorubicin (Dox). Inhibitors were given in a 4 fold molar excess to the substrate studied. To minimize an interaction of the substrates at the hepatic uptake level, the competing compounds were added when over 55% to 85% of the administered dose of the model compounds had been removed from the perfusate and taken up by the liver. We found a mutual interaction between TBuMA and procainamidethobromide (PAEB), both type 1 cationic compounds during biliary excretion. Interestingly, type 2 compounds, such as rocuronium, clearly inhibited type 1 cationic drugs as well as Dox secretion into bile, whereas type 1 compounds did not significantly inhibit type 2 drug excretion into bile. The type 1 cations PAEB and TBuMA only moderately inhibited Dox biliary excretion. Dox did not inhibit the biliary excretion of the type 2 agent rocuronium whereas rocuronium reduced Dox biliary excretion by 50% compared to controls. MDR substrates/reversal agents like verapamil, quinine, quinidine and vinblastine strongly reduced both type 1 and type 2 organic cation excretion into bile. Dox secretion into bile was also profoundly reduced by these drugs, vinblastine being the most potent inhibitor in general. The lack of mutual inhibition observed in some combinations of substrates may indicate that major differences in affinity of the substrates for a single excretory system exist. Alternatively, multiple organic cation transport systems with separate substrate specificities may be involved in the biliary excretion of amphiphilic drugs. Furthermore, the present study revealed a clear positive correlation between the lipophilicity of the potential inhibitors studied and their respective inhibitory activity on the biliary excretion of the model drugs investigated. Our data are compatible with a potential involvement of P‐glycoprotein in the hepatobiliary excretion of doxorubicin as well as of some type 1 and type 2 organic cations. Furthermore we postulate that the hydrophobic properties of the amphiphilic cationic drugs studied play a crucial role in the accommodation of these agents by P‐glycoprotein and/or other potential cationic drug carrier proteins in the canalicular membrane. British Journal of Pharmacology (1998) 123 , 361–370; doi: 10.1038/sj.bjp.0701606
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