Robert E. Dupuis

The influence of norfloxacin and metronidazole on the disposition of mycophenolate mofetil.

The objective of this study was to investigate the effect of concurrent antibiotic administration on the disposition of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG) after oral administration of mycophenolate mofetil (MMF) in healthy subjects. Eleven healthy subjects were enrolled. The study was divided into 4 treatment periods. Subjects received MMF as a single oral 1‐g dose alone and were then randomized to 3 antibiotic treatment periods. The 3 periods included norfloxacin, metronidazole, and a combination of norfloxacin and metronidazole. Antibiotic treatment was started 3 days prior to each MMF pharmacokinetic study day and was given for a total of 5 days. On day 4 of each antibiotic phase, subjects received a single 1‐g oral dose of MMF. Plasma and urine samples were obtained over 48 hours after the MMF dose in all treatment periods and were quantitatively measured for MPA and MPAG. Pharmacokinetic parameters for MPA and MPAG were determined for all periods. Compared to MMF alone, the area under the plasma concentration versus time curve (AUC) of MPA was reduced by an average of 10%, 19%, and 33% when given with norfloxacin, metronidazole, and norfloxacin plus metronidazole, respectively. The AUC of MPAG was also reduced on average by 10%, 27%, and 41% in the corresponding periods. The combination of norfloxacin and metronidazole significantly reduced the AUC of MPA and MPAG in healthy subjects. This likely occurs as a result of reduced enterohepatic recirculation.

Acute Valproic Acid Overdose: Clinical Course and Pharmacokinetic Disposition of Valproic Acid and Metabolites

SummaryAcute toxicity in the setting of valproic acid (valproate sodium) overdose is in most cases benign and readily reversible. However, serious toxicity has been reported. We present a case of accidental acute valproic acid overdose in a 26-month-old female, in whom serious neurological, metabolic, haematological and respiratory sequelae occurred. The major toxicity observed was delayed cerebral oedema. We also present data not previously reported, which describes the pharmacokinetic disposition of valproic acid and several of its metabolites during the course of this acute overdose. A comparison of an enzyme immunoassay and gas liquid chromatographic methodologies for measuring valproic acid in this setting is also presented. It appears that the 2-EN-valproic acid metabolite plays a role in the neurological toxicity.

Determination of mycophenolic acid and its phenol glucuronide metabolite in human plasma and urine by high-performance liquid chromatography

Simultaneous determination of mycophenolic acid (MPA) and mycophenolate phenol glucuronide (MPAG) in plasma and urine was accomplished by isocratic HPLC with UV detection. Plasma was simply deproteinated with acetonitrile and concentrated, whereas urine was diluted prior to analysis. Linearity was observed from 0.2 to 50 microg/ml for both MPA and MPAG in plasma and from 1 to 50 microg/ml of MPA and 5 to 2000 microg/ml MPAG in urine with extraction recovery from plasma greater than 70%. Detection limits using 0.25 ml plasma were 0.080 and 0.20 microg/ml for MPA and MPAG, respectively. The method is more rapid and simple than previous assays for MPA and MPAG in biological fluids from patients.

Valproate metabolites and hepatotoxicity in an epileptic population.

Summary: Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4‐en‐ VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4‐en‐VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4‐en‐VPA correlated with older age and absence of encephalopathy. 4‐en‐VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2‐en‐VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4‐en‐VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4‐en‐VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4‐en‐VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was détécted only in patients receiving polytherapy, a potent risk factor for developing this rare complication.

Multiple Delayed Peak Lithium Concentrations following Acute Intoxication with an Extended-Release Product

OBJECTIVE: To describe delayed peak lithium concentrations after an overdose of extended-release lithium tablets. CASE SUMMARY: a patient with borderline personality disorder and depression ingested extended-release lithium approximately 20.25 g along with other agents. At presentation, the lithium concentration was 1.4 mEq/L. Significant enteral intake was initiated 27 hours after presentation and the lithium concentration 5 hours later increased to 3.2 mEq/L. A second lithium peak concentration of 5.0 mEq/L was noted 40 hours after presentation. Two hemodialysis sessions lasting 4 hours each were performed along with administration of sodium polystyrene sulfonate in sorbitol 20% to enhance lithium elimination and decrease absorption. Eighty-eight hours after presentation, the lithium concentration had decreased to 1.5 mEq/L. DISCUSSION: Delayed and secondary peak lithium concentrations have been reported following an overdose with an extended-release product. Extended-release lithium may form an aggregate in the gastrointestinal tract and/or have delayed absorption secondary to coingested drugs. Toxicity may result if the patient begins enteral intake of drugs, fluids, or nutrition. CONCLUSIONS: Continued monitoring of lithium concentrations after an acute ingestion with an extended-release product are recommended until lithium concentrations are less than 1.5 mEq/L and there are no signs of toxicity, particularly once the patient begins significant enteral intake.

The influence of UGT polymorphisms as biomarkers in solid organ transplantation.

In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive agents such tacrolimus, cyclosporine, sirolimus and everolimus require therapeutic drug monitoring. The study of germline variation of the genome has opened novel opportunities to individualize therapy. Among the currently available immunosuppressive agents, cyclosporine, tacrolimus and mycophenolic acid are in vitro substrates of the UGT1A and 2B families of glucuronidation enzymes. Mycophenolic acid, either given as mycophenolate mofetil or mycophenolate sodium, is the most frequently used antiproliferative immunosuppressant. Mycophenolic acid is a prodrug which is rapidly de-esterified in the gut wall, blood, liver and tissue to the active moiety, mycophenolic acid (MPA). MPA undergoes significant hepatic metabolism to several metabolites. The 7-hydroxyglucuronide MPA is the major metabolite and is inactive. This paper reviews the current status of the genetic associations between germline UGT variants and the pharmacokinetics and pharmacodynamics of mycophenolic acid. Our conclusive assessment of the studies conducted so far is that these germline markers are not ready to be used in the clinic to individualize mycophenolic acid dosing and improve outcome. Novel approaches are required to identify new genetic determinants of outcomes in transplantation.

Tacrolimus-induced pain syndrome in a pediatric orthotopic liver transplant patient

Abstract: Post‐transplant complications are common among patients receiving immunosuppressive medications, including pain syndromes. Recently, a pain syndrome, calcineurin‐inhibitor induced pain syndrome (CIPS) has been described. To our knowledge, this article is the second report of tacrolimus‐associated CIPS, and the first report in the pediatric setting.

Approaches to The Treatment of Hyperlipidemia in the Solid Organ Transplant Recipient

Objective: To review the literature investigating increased lipid concentrations in transplant recipients and the use of lipid-lowering agents in this population. Data Sources: Relevant articles were identified from a MEDLINE search using the terms transplantation, hyperlipidemia, immunosuppression, and therapy including diet, gemfibrozil, bile acid sequestrants, nicotinic acid, probucol, and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Selected literature, including controlled studies, was used in this review. Study Selection: Articles published since 1970 pertaining to hyperlipidemia in solid organ transplant recipients. Emphasis was placed on clinical trials that investigated approaches to the treatment of hyperlipidemia in transplant recipients. Data Extraction: Original articles and reviews were obtained to select material pertinent to the objectives. Data Synthesis: Descriptions of lipid concentrations in the transplant patient and treatment approaches used, including potential complications, were reviewed. Conclusions: Hyperlipidemia is an important risk factor for coronary heart disease in the solid organ transplant patient. Treatment alternatives include diet modification and, in most cases, pharmacologic intervention that should be based on the type of hyperlipidemia. The HMG-CoA reductase inhibitors are effective agents in the treatment of hyperlipidemia in the transplant recipient and generally are used as single therapy in low dosages to minimize the risk of myositis or rhabdomyolysis.

Salivary theophylline monitoring: Reassessment and clinical considerations

Summary To assess the reliability of salivary theophylline concentrations for patient monitoring, concentrations of theophylline in sera and saliva of 50 patients (ages 6–81 years) receiving oral or parenteral theophylline were determined by two methods: a rapid dry-phase apoenzyme reactivation system (ARIS) and fluorescence polarization immunoassay (FPIA). Saliva production was stimulated by both citric acid (CA) and parafilm (PF). With both analytical methods, there were excellent correlations between salivary theophylline concentration, Cs, and unbound serum theophylline concentration Cu (r2 > 0.95), and between Cs and total serum theophylline concentration, CT (r2 > 0.85). CA- and PF-stimulated Cs by FPIA resulted in concentrations within 2.0 μg/ml of the actual Cu for 100% of the samples measured (n = 47). By ARIS, 100% of the PF-stimulated Cs and 93.6% of the CA-stimulated Cs determinations were within 2.0 μg/ml of the Cu (n = 47). To evaluate the predictive capabilities of PF- and CA-stimulated saliva, one-half (n = 24) of the patients were randomly selected and their data used to predict the CT for the remaining patients. FPIA PF-CS predicted 83.3% (20/24) of CT within ±2 μg/ml, while ARIS CA-CS predicted 75.0% within ±2 μg/ml. There was no difference between FPIA Cs and ARIS Cs results by multivariate analysis of variance (MANOVA), but there was a difference between PF-CS and CA-Cs (p < 0.05). However, when Cu was used as a covariant, there was no significant difference. Using appropriate saliva collection procedures and the FPIA system, we conclude that Cs provides adequate reliability for therapeutic drug monitoring of theophylline.

An eight-year retrospective study in “flipped” pharmacokinetics courses

Objective. To assess the impact on student performance of increased active learning strategies in a foundational pharmacokinetics course and a clinical pharmacokinetics course over an 8-year period. Design. A foundational pharmacokinetics course with a lecture-with-active-learning (LAL) format was redesigned to a recitation-format (REC) using smaller groups of students (ie, the class divided into thirds) and eventually to a team-based learning (TBL) format. The lecture-based clinical pharmacokinetics course was redesigned to a case-based learning (CBL) format to encourage preclass preparation with class time used for application; this course format underwent minor redesigns over an 8-year period. An analysis of covariance (ANCOVA) was performed on examination scores in the clinical course based on foundational course format changes. End-of-semester student evaluations of the course were used as a secondary measure of impact. Assessment. The highest grades in the clinical course were associated with the TBL format within the foundational course compared to LAL format (effect size 0.78). The REC format in the foundational course compared to LAL was associated with higher performance in the clinical course (effect size 0.50). Examination performance in the clinical course had a small increase when the foundational course was transitioned from the REC format to the TBL format (effect size 0.27). There was a trend within the foundational course that overall student ratings of the course decreased with enhanced self-directed learning; there was no change in overall ratings of the clinical course. Conclusion. Increasing the amount of active learning within the foundational pharmacokinetics course increases performance in the clinical course but this increase in performance may be associated with decreases in student evaluations of the foundational course.