China 
Africa 
Explore chapters and articles related to this topic
Immunosuppressants, rheumatic and gastrointestinal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Pharmacokinetics. Tac is also a substrate of P-gp and CYP3A4 [20]. Due to first-pass effect, drug absorption is poor and variable, the peak concentration occurring between 0.5 and 4 hours. The drug is highly bound to plasma proteins (75 - 90%) and red blood cells, with a high blood to plasma ratio (12:1). Metabolism by CYP3A, both in the liver and the gut, is followed by biliary excretion. At least 10 metabolites are formed, some of which retain significant activity [21]. Paediatric patients have a higher volume of distribution and a higher clearance than adults. The mean total body clearance normalised to bodyweight in paediatric patients is 0.14 L/h/kg after intravenous administration following liver transplantation (Table 1). This was approximately double the value observed in adult liver transplant patients of 0.06 L/h/kg [21].
Clinical Trials with Anti-p53 DNA, OL(1)p53, in Patients with Acute Myelogenous Leukemia and Myelodysplastic Syndrome
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
The whole blood-to-plasma ratio was greater than 0.9 indicating little of the compound is associated with circulating red blood cells in whole blood. The OL(l)p53 concentration in the peripheral blood mononuclear cell (PBMC) fraction from one patient that was administered uniformly labeled phosphorothioate oligonucleotide was determined. The average cell volume of PBMCs is 55.1 x 1011 liters and the average PBMC concentration of OL(l)p53 at steady state was 38.8 ± 9-6 μΜ. This concentration is well beyond the concentration required to induced cytotoxicity in leukemic blast cells in cell culture. No significant correlation was observed between the change in the number of circulating PBMCs and plasma concentration of OL(l)p53. The same was true for the number of detected blast cells in peripheral blood. However, there is a linear relationship in long-term bone marrow cultures of the mononuclear fraction from bone marrow aspirates in which a decrease in cellularity was observed with dose (Bishop et al., 1996).
Bottom-up physiologically based pharmacokinetic modelling for predicting the human pharmacokinetic profiles of the ester prodrug MGS0274 and its active metabolite MGS0008, a metabotropic glutamate 2/3 receptor agonist
Published in Xenobiotica, 2022
Motoki Ochi, Kohnosuke Kinoshita, Jun-ichi Yamaguchi, Hiromi Endo
The blood-to-plasma ratios of MGS0274 and MGS0008 were analysed using pooled fresh whole blood and control plasma separated from fresh whole blood from humans. The anticoagulants used for MGS0274 and MGS0008 were sodium heparin and dipotassium ethylene diamine tetraacetate, respectively. Whole blood and control plasma containing 2.5 or 250 nM of MGS0274 besylate or 3 μM of MGS0008 were incubated at 37 °C for 30 minutes in a shaking water bath. The incubated whole blood was centrifuged at 2,000 ×g for 10 minutes at 4 °C to obtain plasma samples. An aliquot of each plasma sample (that is, isolated plasma from incubated whole blood and control plasma) was mixed with eight volumes of acetonitrile/methanol/formic acid (90:10:1, v/v/v) containing [2H4]MGS0274 and [13C215N]MGS0008 as each IS for bioanalysis. After centrifugation at 3,974 ×g for 10 minutes at 4 °C, the supernatant was subjected to bioanalysis by LC-MS/MS. The blood-to-plasma ratio was calculated by dividing the concentration in the control plasma, which was the same as that in whole blood, by that in the plasma obtained by centrifugation from the incubated whole blood.
Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (−)-lumefantrine and (+)-lumefantrine in mice
Published in Xenobiotica, 2021
Bhavesh Babulal Gabani, Abhishek Dixit, Vinay Kiran, Ram Murthi Bestha, Balaji Narayanan, Nuggehally R. Srinivas, Ramesh Mullangi
Aliquots of fresh whole mice or human blood (hematocrit value of 45 and 47% in mice and human blood, respectively) and control plasma (separated from fresh whole blood in parallel) were spiked with (−)-LFN, (+)-LFN and chloroquine at 1 μM or rac-LFN at 2 μM and then incubated for 30 min at 37 °C on a Julabo shaking water bath. After completion of the incubation period, plasma was separated from the incubated whole blood. Three aliquots of each sample were processed and the concentration of the target analytes samples was analyzed by LC-MS/MS. The value of blood to plasma ratio (KWB/P) was calculated for each analyte (Yu et al. 2005). We were unable to perform the blood partitioning experiment at higher concentrations owing to the solubility limitation of LFN and therefore, it was restricted to a single concentration where the highest solubility of the drug was achieved.
Human mass balance, pharmacokinetics and metabolism of rovatirelin and identification of its metabolic enzymes in vitro
Published in Xenobiotica, 2019
Kaoru Kobayshi, Yoshikazu Abe, Asuka Kawai, Takao Furihata, Hiroshi Harada, Takuro Endo, Hiroo Takeda
The highest concentration of rovatirelin in plasma was observed at 5.02 h after administration, which was almost the same as that of total radioactivity in plasma, and the concentration decreased with a t1/2 of 14.9 h (Table 1 and Figure 1). Conversely, rovatirelin was rapidly absorbed after oral administration to rats and dogs (tmax: 0.4–0.6 h after administration in rats, 1.0 h after administration in dogs), and t1/2 was 3.3–7.7 h in rats and 2.7 h in dogs (Kobayashi et al., 2019). These findings illustrate that rovatirelin is likely to be steadily absorbed and slowly eliminated from plasma in humans. Similar to the blood-to-plasma ratio (Rb: 0.815–0.828) in an in vitro study (Kobayashi et al., 2019), Rb in this mass balance study was as low as 0.713–0.771, exhibiting a limited degree of partitioning of drug-related material into blood cells in vivo. The urinary excretion of rovatirelin up to 12 h after administration was 71% relative to the total radioactivity in urine, revealing that rovatirelin was mainly excreted in urine at early times after administration (Figure 2).