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Mycophenolate mofetil (MMF) is an effective immunosuppressant usually used in renal transplantation to prevent acute rejection. It is quickly hydrolized to mycophenolic acid (MPA), which is pharmacologically active. MPA is then converted mainly to an inactive glucuronide metabolite (MPAG), an acyl glucuronide (M2) which has been shown active in vitro, and to two other metabolites. MPA is highly bound to HSA and only the free fraction is active. We validate an analytical method specific for measurement of MPA and MPAG by HPLC. The EMIT methodology offers the opportunity to determine both MPA and M2 metabolite. The determination of free MPA can be achieved by a modified EMIT program after plasma ultrafiltration. We confirmed variation of pharmacokinetic parameters among transplant patients, associated with cyclosporin (CsA) or tacrolimus (Tc) based immunosuppression. 51 MPA-PK profiles (0, 0.5, 1, 2, 4, 6, 12h after oral dose) were obtained. The following PK parameters were increased in the Tc-based immunosuppression as compared to CsA : Cmax: 30.12 ±27.52 vs 11.69± 7.06 mg/L (p< 0.001); AUC MPA 114.10±40.95 vs 43.68±20.48 mg. h/L (p<0.001); t1/2 : 6.40 ± 2.98 vs 3.35 ± 1.41 h (p<0.01). In the CsA based immunosuppression we observed an increase of M2 : 32.57±14.42 vs 20.35± 13.02 % (p=0.004); and of clearance of MPA : 358.49±123.75 vs 137.31±33.02 ml/min. These results provided evidence that interaction between MMF and Tc or CsA exists and is probably related to a possible inhibitory effect of Tc on MPA metabolism and to an inhibition of the enterohepatic recirculation of MPA by CsA. Alteration of the MPA pharmacokinetics is also associated with renal function. The results of renal impairment are expressed by an increased AUC0-12 MPAG, MPA free fraction, and AUC0-12 of free fraction. As expected negative correlations were found between MPAG AUC and creatinine clearance (r=-0.48), between MPAf AUC and creatinine clearance (r=-0.48). So, these significant variations of pharmacokinetic parameters are important because of the correlation between MPA concentration and therapeutic/toxic effects Indeed, high MPA Cmin, C30, C60 increase side effects. Finally, individual variabilities, the change over time in MPA-pharmacokinetic parameters and PK-PD relationship are good arguments for MPA concentration monitoring which would improve patient outcome. Le mycophénolate mofétil (MMF) est un immunosuppresseur couramment utilisé en transplantation rénale dans la prévention du rejet aigu. Il est rapidement hydrolysé en acide mycophénolique (MPA) qui est pharmacologiquement actif. Différents métabolites du MPA ont été identifiés dont, entre autre, le MPAG, glucuronoconjugué phénolique du MPA pharmacologiquement inactif et récemment le M2 montré actif in vitro. Le MPA est fortement lié aux protéines sériques et uniquement la fraction libre est active. Nous avons mis au point une méthode de dosage spécifique du MPA et du MPAG par HPLC. Le MPA peut également être dosé par EMIT, en même temps que le M2. En faisant la différence entre ces 2 méthodes, on peut déterminer le M2. Un programme modifié de l’EMIT nous permet de doser la fraction libre. Nous avons confirmé les variations des propriétés pharmacocinétiques (PK) du MPA suivant l’administration d’un inhibiteur de la calcineurine, comme la cyclosporine (CsA) ou le tacrolimus (Tc). Dans une population de greffés rénaux sous MMF associé soit à la CsA soit au Tc, nous avons obtenu 51 profils pharmacocinétiques de MPA (temps : 0, 0.5, 1, 2, 4, 6, 12h après la dose orale). Les paramètres suivants ont augmentés en association avec le Tc par rapport au traitement associant la CsA : Cmax : 30.12 ±27.52 vs 11.69±7.06 mg/L (p< 0.001); AUC MPA 114.10±40.95 vs 43.68±20.48 mg. h/L (p<0.001); t1/2 : 6.40 ± 2.98 vs 3.35 ± 1.41 h (p<0.01). D’autre part, sous Csa, on observe une augmentation de M2 : 32.57±14.42 vs 20.35±13.02 % (p=0.004); et de la clairance du MPA : 358.49±123.75 vs 137.31±33.02 mL/min. Ces résultats illustrent clairement l’interaction médicamenteuse existant entre le MMF et la cyclosporine ou le tacrolimus. Soit la cyclosporine entraîne une induction métabolique importante (visible par l’augmentation de clairance, la réduction de l’AUC…) et/ou une réduction de biodisponibilité (inhibition du cycle entérohépatique), soit le tacrolimus entraîne une inhibition métabolique. Les PK du MPA varient également en fonction de l’insuffisance rénale. Le MPAG s’accumule et la fraction libre augmente : corrélation négative entre l’AUC du MPAG et la clairance à la créatinine (r= -0.48), et entre l’AUC du MPAf et la clairance à la créatinine (r=-0.48). Ces importantes variations des PK auraient peu d’intérêt sans l’existence d’une corrélation entre les taux plasmatiques de MPA et les effets thérapeutiques et/ou toxiques du MPA. Or il apparaît que des grandes valeurs pour Cmin, C30, C60 sont associées à un risque accru d’effets secondaires. Enfin, les variations des PK du MPA ainsi que la relation pharmacocinétique/pharmacodynamique sont deux points importants en faveur du monitoring thérapeutique

Kidney Transplantation --- Drug Monitoring --- Mycophenolic acid

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Mycophenolic acid --- Transplantation of organs, tissues, etc --- Immunotherapy --- Immunologic Factors --- Therapeutics --- Host vs Graft Reaction --- Investigative Techniques --- Fatty Acids --- Caproates --- Transplantation --- Immunologic Techniques --- Acids, Acyclic --- Transplantation Immunology --- Physiological Effects of Drugs --- Diagnostic Techniques and Procedures. --- Surgical Procedures, Operative --- Immunomodulation --- Lipids --- Pharmacologic Actions --- Biological Therapy --- Carboxylic Acids --- Organic Chemicals --- Immune System Phenomena --- Chemical Actions and Uses --- Mycophenolic Acid --- Immunosuppression Therapy --- Immunosuppressive Agents --- Organ Transplantation --- Graft Rejection --- Methods --- Drug Therapy --- Health & Biological Sciences --- Pharmacy, Therapeutics, & Pharmacology --- Complications

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Mycophenolic acid --- Transplantation of organs, tissues, etc --- Immunotherapy --- Immunologic Factors --- Therapeutics --- Host vs Graft Reaction --- Investigative Techniques --- Fatty Acids --- Caproates --- Transplantation --- Immunologic Techniques --- Acids, Acyclic --- Transplantation Immunology --- Physiological Effects of Drugs --- Diagnostic Techniques and Procedures. --- Surgical Procedures, Operative --- Immunomodulation --- Lipids --- Pharmacologic Actions --- Biological Therapy --- Carboxylic Acids --- Organic Chemicals --- Immune System Phenomena --- Chemical Actions and Uses --- Mycophenolic Acid --- Immunosuppression Therapy --- Immunosuppressive Agents --- Organ Transplantation --- Graft Rejection --- Methods --- Drug Therapy --- Complications --- Transplantation of organs, tissues, etc. --- Immunotherapy. --- Immunologic Factors. --- Therapeutics. --- Host vs Graft Reaction. --- Investigative Techniques. --- Fatty Acids. --- Caproates. --- Transplantation. --- Immunologic Techniques. --- Acids, Acyclic. --- Transplantation Immunology. --- Physiological Effects of Drugs. --- Surgical Procedures, Operative. --- Immunomodulation. --- Lipids. --- Pharmacologic Actions. --- Biological Therapy. --- Carboxylic Acids. --- Organic Chemicals. --- Immune System Phenomena. --- Chemical Actions and Uses. --- Mycophenolic Acid. --- Immunosuppression Therapy. --- Immunosuppressive Agents. --- Organ Transplantation. --- Graft Rejection. --- Methods. --- Drug Therapy. --- Complications.

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Olesja Rissling analyzes the potential interaction of mycophenolic acid (MPA) and pantoprazole. MPA is used as an immunosuppressive drug to prevent acute organ rejections after organ transplantation. Pantoprazole, known to interact with the bioavailability of drugs, is used to prevent upper gastrointestinal disorders. The author performed a clinical pharmacokinetic study in renal transplant patients to evaluate a potential interaction of MPA and pantoprazole. The bioavailability and the maximum concentration of MPA were determined with or without pantoprazole intake. An influence on the immunosuppressive effect was evaluated by measuring the target enzyme activity. Overall, no significant change in the bioavailability or the maximum concentration was found. Similar results were obtained for the target enzyme activity after pantoprazole intake with MPA. The results suggest that the interaction of pantoprazole with MPA does not compromise the immunosuppressive effect to a clinically meaningful extent. Contents Validation of an Assay for Quantification of MPA and MPAG Clinical Study of a PK Interaction of Pantoprazole and MPA Bioequivalence Analysis Target Groups Researchers and students in the fields of medicine and pharmacy Practitioners in the fields of nephrology and clinical pharmacology The Author Olesja Rissling studied pharmacy and works as a research associate at the Federal Joint Committee in the field of benefit assessment of pharmaceuticals. .

Medicine. --- Laboratory medicine. --- Pharmacology. --- Biomedicine. --- Pharmacology/Toxicology. --- Laboratory Medicine. --- Mycophenolic acid. --- Drug interactions. --- Interactions, Drug --- Drugs --- Mycophenolate --- Mycophenolate mofetil --- Antirheumatic agents --- Immunosuppressive agents --- Side effects --- Toxicology. --- Medical laboratories. --- Diagnosis, Laboratory --- Health facilities --- Laboratories --- Chemicals --- Medicine --- Pharmacology --- Poisoning --- Poisons --- Toxicology --- Clinical medicine --- Clinical pathology --- Diagnostic laboratory tests --- Laboratory diagnosis --- Laboratory medicine --- Medical laboratory diagnosis --- Diagnosis --- Pathology --- Drug effects --- Medical pharmacology --- Medical sciences --- Chemotherapy --- Pharmacy --- Physiological effect

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Since its early introduction by the Russian botanist Mikhail Semyonovich Tsvet, chromatography has been undoubtedly the most powerful analytical tool in analytical chemistry. Separation, qualitative analysis, and quantitative analysis can be achieved by choosing the right conditions. Thus, numerous gas chromatographic, liquid chromatographic, and supercritical fluid chromatographic methods have been developed and applied for most types of samples and most kinds of analytes. Additionally, older varieties such as paper chromatography and thin-layer chromatography were pioneer analytical techniques in many laboratories. Especially when hyphenated to spectrometric techniques, chromatography also allows the identification of separated analytes in a single run. Highly sophisticated equipment can answer all analytical problems very quickly. Chromatographers cooperate with many scientific fields and give their lights to medical doctors, veterinarians, food scientists, biologists, dentists, archaeologists, etc. In this Special Issue, analytical chemists were invited to prove that chromatography-based separation techniques are the ultimate analytical tool and their significant contribution is reflected in ten interesting articles.

polyamine --- steroid --- breast cancer --- liquid chromatography–tandem mass spectrometry --- serum --- photoaging --- proteomics --- genomics --- Swietenia macrophylla --- UV irradiation --- keratinocytes --- epidermal layer --- cosmetics --- natural product --- LC-MS/MS --- metabolomics --- targeted analysis --- nontargeted analysis --- sample preparation --- derivatization --- validation --- biomarkers --- mycophenolate mofetil --- mycophenolic acid --- pediatric patients --- limited sampling strategy --- multiple linear regression --- therapeutic drug monitoring --- almonds --- HPLC --- authenticity --- PCA --- tocopherols --- phenolics --- method validation --- Miang --- catechins --- caffeine --- gallic acid --- walnut septum --- UAE --- SPE --- flavonoids --- functional --- HPLC-DAD --- biotin acceptor peptide (BAP) --- biotin ligase BirA --- liquid chromatography tandem mass spectrometry (LC-MS/MS) --- multiple reaction monitoring (MRM) --- protein–protein interactions (PPIs) --- proximity utilizing biotinylation (PUB) --- greener HPTLC --- paracetamol --- simultaneous determination --- microflow LC-MS --- mLC-MS/MS --- liver fibrosis --- hemopexin --- biomarker