Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses.

BACKGROUND: In humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency. RESULTS: Morphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied. CONCLUSIONS: The current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.

New Perspectives on Drug-Induced Liver Injury Risk Assessment of Acyl Glucuronides.

Drug-induced liver injury (DILI) remains one of the key challenges in drug development due to the mechanisms of action being multifactorial in nature. This is particularly the case for idiosyncratic DILI which occurs in a very low frequency in humans (e.g., 1:10,000). Despite perceptions that acyl glucuronide metabolites are defacto risks for DILI, scientific evidence suggests that acyl glucuronide formation alone does not pose an increased risk compared to other drug metabolites. This applies in particular to those acyl glucuronides which are not reactive and do not form covalent adducts with proteins. The goal of this paper is to provide guidance on preclinical and clinical strategies to evaluate the potential for acyl glucuronide formation to contribute to DILI. A key element of our proposed safety assessment is to investigate whether a particular acyl glucuronide is reactive or not and whether systemic exposure in humans can be demonstrated in animal toxicology studies following administration of the parent drug. While standard animal toxicology studies can identify overtly hepatotoxic compounds, these studies are not predictive for drugs that produce idiosyncratic forms of DILI. In addition, we do not recommend conducting toxicology studies of administered individual acyl glucuronides due to differences in pharmacokinetic and dispositional properties from the endogenously produced metabolites. Once a drug candidate has entered clinical trials, the focus should be on clinical safety data and emerging risk-benefit analysis.

Serum metabolomic profiling reveals potential biomarkers in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored. METHODS: High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis. RESULTS: The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis. CONCLUSIONS: Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.

7-hydroxycoumarin-ß-D-glucuronide protects against cisplatin-induced acute kidney injury via inhibiting p38 MAPK-mediated apoptosis in mice.

AIMS: Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-ß-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. MATERIALS AND METHODS: Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. KEY FINDINGS: 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t1/2ß of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. SIGNIFICANCE: Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.

Acyl glucuronides: the good, the bad and the ugly.

Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response.

Roles of diclofenac and its metabolites in immune activation associated with acute hepatotoxicity in TgCYP3A4/hPXR-humanized mice.

Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug, but it comes with a high risk of drug-induced liver injury (DILI). Despite the quinone-imine adduct pathways, the immunotoxicity is recently considered as another factor for DILI. However, such immune responses are still elusive. In the present study, investigation of the immune response in the acute hepatotoxicity model of TgCYP3A4/hPXR-humanized mice was conducted by administration of DCF and DCF metabolites, respectively. In a single dose intraperitoneal injection of 80 mg/kg DCF, the pharmacokinetic results showed the major DCF metabolites, including 4'-hydroxy-diclofenac (4'-OH-DCF), 5-hydroxy-diclofenac (5-OH-DCF) and diclofenac glucuronide (DCF-G) were generated after DCF treatment. Not only DCF, but those DCF metabolites could also directly cause different degrees of acute liver injury as significantly increased the serum ALT levels in a short time period in the TgCYP3A4/hPXR-humanized mice. Furthermore, the three DCF metabolites could directly stimulate the significant elevation of serum immune-related factors in varying degrees. Transcriptome analysis revealed the differentially expressed genes in the liver of DCF-G treated mice were mostly involved with the "immune system process" and "cell death" and related to "IL-17 signaling pathway" and "TNF-α signaling pathway", but 5-OH-DCF had little effect on the expressions of those genes. These results indicate that the metabolite DCF-G plays an important role in the activation of the hepatic immune system, which might be involved in the pathogenesis of DCF-induced acute liver injury.

Comparative Evaluation of Median Versus Youden Index Dichotomization Methods: Exposure-Response Analysis of Mycophenolic Acid and Acyl-Glucuronide Metabolite.

BACKGROUND AND OBJECTIVES: Dichotomization of pharmacokinetic exposure measures in exposure-response relationship studies provides results that are interpretable in clinical care. Several methods exist in the literature on how to define the cut-off values needed for the dichotomization process. Commonly, the sample median is utilized to define the dichotomizing value; however, statistical methods based on the exposure metric and its association with the outcome are argued to result in a more proper definition of the optimal cut-point. The Youden index is a recommended statistical method to define the cut-off value. The current analysis objective is to compare the dichotomization results based on the Youden index versus median methods. METHODS: Utilizing mycophenolic acid (MPA) exposure data and its related acute rejection and leukopenia outcome variables, the current study compared the MPA exposure-response relationship outcomes when MPA exposure is dichotomized via the Youden index versus median methods. Univariate logistic models were utilized to quantify the relationships between MPA exposure, including total MPA, unbound MPA, and the acyl-glucuronide metabolite of MPA, and the probabilities of acute rejection and leukopenia. RESULTS: The overall trend of the results of the logistic models demonstrated a general similarity in the inferred exposure-response associations when considering either the Youden index-based or the median-based dichotomization methods. CONCLUSION: The results demonstrated in this analysis suggest that both the Youden index and the median methods provide similar conclusions when dichotomization of a continuous variable is considered. However, confirmation of these conclusions comes from future powered studies that include a larger number of subjects.

Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea.

The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.

Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients.

BACKGROUND AND OBJECTIVES: No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus METHODS: The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. RESULTS: Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. CONCLUSION: Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.

[Optimization of Immunosuppression and the Prevention of Fungal Infection in Autoimmune Diseases].

Mycophenolate mofetil (MMF) has recently been reported to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG), and factors affecting their pharmacokinetics, remain to be clarified. The influence of the pharmacokinetics of MPA and MPAG on the activity of inosine 5'-monophosphate dehydrogenase (IMPDH), a target of the MPA, also remains to be revealed. The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole frequently co-administered with immunosuppressants in immunocompromised patients, is not fully known. The aim of this study was to establish the optimal dosage and administration of immunosuppressants and antifungal agents. MMF improved clinical laboratory markers and reduced prednisolone dosage in 31 SLE patients, with a pre-dose plasma concentration of MPA and MPAG in the interquartile ranges of 0.94-2.96 and 18.6-53.7 µg/mL, respectively. Renal function and co-administered metal influenced the pharmacokinetics of MPA and MPAG in 31 SLE patients in the remission maintenance phase. IMPDH activity was induced in 29 SLE patients receiving the MMF therapy. This induction was dependent on the plasma concentration of MPAG, but not MPA. In addition, IMPDH activity was negatively correlated with complement fraction C3. MPA exposure and disease activity in SLE patients may determine IMPDH activity. The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-itraconazole, serum concentration of albumin, and renal function in 46 immunocompromised patients. Prevention of fungal infections and drug-drug interactions in immunocompromised patients can be obtained by considering these identified confounding factors.

Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions.

Some carboxylic acid-containing drugs have been implicated in rare but serious adverse reactions. These compounds can be bioactivated via two distinct pathways: by UDP-glucuronosyltransferase-catalyzed conjugation with glucuronic acid, resulting in the formation of acyl glucuronides, or by acyl-CoA synthetase-catalyzed formation of acyl-CoA thioesters. This review compares the two types of potentially reactive metabolites with respect to their stability, protein-reactivity, target selectivity, and disposition in the liver, and summarizes the evidence which links acyl glucuronide and acyl-CoA thioester formation with downstream toxicologic effects. While with increasing drug concentration the acyl glucuronide pathway may prevail, CoA intermediates may be more reactive. Both metabolites are electrophilic species which can acylate target proteins if they escape inactivation by S-glutathione-thioester formation. A crucial factor is the up-concentration of acyl glucuronides in hepatocytes and the biliary tree, due to vectorial transport by conjugate export pumps, where they may selectively acylate canalicular membrane proteins. Furthermore, positional isomers, which are avidly formed by acyl migration, can glycate proteins in the liver and at more distal sites. In contrast, acyl-CoA esters may be more rapidly hydrolysed or further metabolized in hepatocytes, and their hepatobiliary transport has not been well explored. While there is accumulating evidence that acyl glucuronides can alter cellular function by various mechanisms, including haptenation of peptides, critical protein acylation or glycation, or direct stimulation of neutrophils and macrophages, the role of acyl-CoA intermediates is less clear. More work is needed to provide a causal link between protein-reactive acyl glucuronides and acyl-CoA thioesters and the rare and unpredictable idiosyncratic drug reactions in humans.

Acyl glucuronide reactivity in perspective: biological consequences.

The metabolic conjugation of exogenous and endogenous carboxylic acid substrates with endogenous glucuronic acid, mediated by the uridine diphosphoglucuronosyl transferase (UGT) superfamily of enzymes, leads to the formation of acyl glucuronide metabolites. Since the late 1970s, acyl glucuronides have been increasingly identified as reactive electrophilic metabolites, capable of undergoing three reactions: intramolecular rearrangement, hydrolysis, and intermolecular reactions with proteins leading to covalent drug-protein adducts. This essential dogma has been accepted for over a decade. The key question proposed by researchers, and now the pharmaceutical industry, is: does or can the covalent modification of endogenous proteins, mediated by reactive acyl glucuronide metabolites, lead to adverse drug reactions, perhaps idiosyncratic in nature? This review evaluates the evidence for acyl glucuronide-derived perturbation of homeostasis, particularly that which might result from the covalent modification of endogenous proteins and other macromolecules. Because of the availability of acyl glucuronides for test tube/in vitro experiments, there is now a substantial literature documenting their rearrangement, hydrolysis and covalent modification of proteins in vitro. It is certain from in vitro experiments that serum albumin, dipeptidyl peptidase IV, tubulin and UGTs are covalently modified by acyl glucuronides. However, these in vitro experiments have been specifically designed to amplify any interference with a biological process in order to find biological effects. The in vivo situation is not at all clear. Certainly it must be concluded that all humans taking carboxylate drugs that form reactive acyl glucuronides will form covalent drug-protein adducts, and it must also be concluded that this in itself is normally benign. However, there is enough in vivo evidence implicating acyl glucuronides, which, when backed up by in vivo circumstantial and documented in vitro evidence, supports the view that reactive acyl glucuronides may initiate toxicity/immune responses. In summary, though acyl glucuronide-derived covalent modification of endogenous macromolecules is well-defined, the work ahead needs to provide detailed links between such modification and its possible biological consequences.

Uncertainty factors for chemical risk assessment: interspecies differences in glucuronidation.

For the risk assessment of effects other than cancer, a safe daily intake in humans is generally derived from a surrogate threshold dose (e.g. NOAEL) in an animal species to which an uncertainty factor of 100 is usually applied. This 100-fold is to allow for possible interspecies (10-fold) and interindividual (10-fold) differences in response to a toxicant, and incorporates toxicodynamic and toxicokinetic aspects of variability. The current study determined the magnitude of the interspecies differences in the internal dose of compounds for which glucuronidation is the major pathway of metabolism in either humans or in the test species. The results showed that there are major interspecies differences in the nature of the biological processes which influence the internal dose, including the route of metabolism, the extent of presystemic metabolism and enterohepatic recirculation. The work presented does not support the refinement of the interspecies toxicokinetic default to species- and pathway-specific values, but demonstrates the necessity for risk assessments to be carried out using quantitative chemical-specific data which define the fundamental processes which will influence the internal dose of a chemical (toxicokinetics), or the interaction of toxicant with its target site (toxicodynamics).

An update on uremic toxins.

In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

Pharmacokinetics of oral tonapofylline and its acyl-glucuronide metabolite in patients with mild and moderate hepatic impairment.

The objective of the study was to evaluate the effect of hepatic impairment on the pharmacokinetics of tonapofylline. Patients with mild or moderate hepatic impairment were enrolled in parallel with demographically matched healthy subjects. All study participants received a single 75-mg oral tonapofylline capsule. The pharmacokinetic parameters for both tonapofylline and its active metabolite, acyl-glucuronide (tonapofylline-AG), were affected by hepatic impairment significantly (P < .1) except for time to peak plasma concentration (t(max)), terminal half-life (t(½)), and apparent volume of distribution based on the terminal phase (Vdz/F). In the mild group, peak plasma concentration (C(max)), area under the time-concentration curve from time 0 to 48 hours postdose (AUC(48 h)), and from time 0 to infinity (AU(Cinf)) of tonapofylline modestly increased as compared with the control healthy subjects (GMR 1.62, 1.57, and 1.53, respectively). The extent of increase of these parameters for tonapofylline-AG was more profound than tonapofylline with geometric mean ratio (GMR) ranging from 2.02 to 2.08. Moderate hepatic impairment was also associated with modest increases of C(max), AUC(48 h), and AUC(inf) of tonapofylline (GMR 1.41, 1.98, and 2.08, respectively). Similar to the mild group, the increase of these parameters were higher for tonapofylline-AG with GMR ranging from 2.80 to 3.86. Single oral 75-mg tonapofylline was safe and well tolerated in patients with mild or moderate hepatic impairment.

Plasma concentrations of mycophenolic acid acyl glucuronide are not associated with diarrhea in renal transplant recipients.

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.