Complex Pharmacokinetic Profile Research Articles

Amiodarone Therapy: Updated Practical Insights.

Amiodarone, a bi-iodinated benzofuran derivative, is among the most commonly used antiarrhythmic drugs due to its high level of effectiveness. Though initially categorized as a class III agent, amiodarone exhibits antiarrhythmic properties across all four classes of antiarrhythmic drugs. Amiodarone is highly effective in maintaining sinus rhythm in patients with paroxysmal atrial fibrillation while also playing a crucial role in preventing a range of ventricular arrhythmias. Amiodarone has a complex pharmacokinetic profile, characterized by a large volume of distribution and a long half-life, which can range from several weeks to months, resulting in prolonged effects even after discontinuation. Side effects may include thyroid dysfunction, pulmonary fibrosis, and hepatic injury, necessitating regular follow-ups. Additionally, amiodarone interacts with several drugs, including anticoagulants, which must be managed to prevent adverse effects. Therefore, a deep understanding of both oral and intravenous formulations, as well as proper dosage adjustments, is essential. The aim of this paper is to provide a comprehensive and updated review on amiodarone's indications, contraindications, recommended dosages, drug interactions, side effects, and monitoring protocols.

Evaluation of Goal Phenytoin Levels After an Initial Intravenous Loading Dose at an Academic Medical Center.

Phenytoin intravenous loading doses are administered in status epilepticus to rapidly achieve therapeutic levels. Accurately assessing phenytoin levels after the initial load can be challenging because of its complex pharmacokinetic profile and nonstandardized weight-based loading doses. The objectives of this analysis were to determine the incidence of patients achieving goal phenytoin levels after the initial loading dose and characterize factors that contribute to achieving the goal level. This single-center, retrospective cohort analysis was approved by our institutional review board and included adult patients who received a phenytoin load from May 2016 to March 2021. Patients were excluded if no total phenytoin level was drawn within 24 hours of the load, if the maintenance dose was given before the first level was drawn, or if the patient was on phenytoin before the load. The major endpoint was the percentage of patients achieving a corrected goal phenytoin level of ≥10 mcg/mL after the initial load. Multivariate regression was used to determine predictors of achieving the goal phenytoin level. Of the 152 patients included, 139 patients (91.4%) achieved a corrected goal level after the first load. Patients at goal received a significantly higher median weight-based loading dose (19.1 mg/kg [15.0-20.0] vs 12.6 mg/kg [10.1-15.0], P < 0.01). The multivariate analysis identified weight-based dosing as a statistically significant predictor of achieving the corrected goal level (odds ratio, 1.30; 95% CI, 1.12-1.53; P < 0.01). Most patients achieved a corrected goal phenytoin level after the initial load. A higher median weight-based loading dose was shown to be a predictor of achieving the goal level and should be encouraged for rapid seizure termination. Future studies are warranted to confirm patient-specific factors that affect rapid achievement of the goal phenytoin level.

Dosage optimization of voriconazole in children with haematological malignancies based on population pharmacokinetics.

Voriconazole has a complex pharmacokinetic profile and exhibits different pharmacokinetic characteristics in adults and children. Nevertheless, few studies have been conducted on the population pharmacokinetics (PPK) of voriconazole in children with haematological malignancies. This study aims to build a PPK model and propose a suitable voriconazole treatment scheme for children with haematological malignancies. We retrospectively collected 146 samples from 67 children aged from 1.08 to 17.92 years. The PPK model was established using nonlinear mixed effects modelling (NONMEM). Dosage simulations were conducted on the basis of the final model's covariates. Data were fully characterized by a one-compartment model with first-order absorption and elimination. The weight (WT), CYP2C19 phenotype, and Albumin (ALB) were notable covariates for clearance (CL). The typical values of CL, the volume of distribution (V), and oral bioavailability (F) were 2.29 L/h, 76 L, and 0.902, respectively. The proposed doses for different CYP2C19 genotypes were presented in this ranking: EM (extensive metabolizer) > IM (intermediate metabolizer) > PM (poor metabolizer). Furthermore, higher dosages for light WT patients were recommended while lower ALB levels required lower doses. The probability of achieving the target (PTA) for the recommended doses ranged from 72.2% to 99%. We successfully built a voriconazole PPK model for children with hematologic malignancies. Dosing regimens were developed for different patients based on the final model, which could enhance the rational use of voriconazole in children with haematological malignancies.

Naturally-Occurring Bioactives in Oral Cancer: Preclinical and Clinical Studies, Bottlenecks and Future Directions.

Oral cancer (OC) is the eighth most common cancer, particularly prevalent in developing countries. Current treatment includes a multidisciplinary approach, involving chemo, radio, and immunotherapy and surgery, which depends on cancer stage and location. As a result of the side effects of currently available drugs, there has been an increasing interest in the search for naturally-occurring bioactives for treating all types of cancer, including OC. Thus, this comprehensive review aims to give a holistic view on OC incidence and impact, while highlights the preclinical and clinical studies related to the use of medicinal plants for OC prevention and the recent developments in bioactive synthetic analogs towards OC management. Chemoprophylactic therapies connect the use of natural and/or synthetic molecules to suppress, inhibit or revert the transformation of oral epithelial dysplasia (DOK) into oral squamous cell carcinoma (OSCC). Novel searches have underlined the promising role of plant extracts and phytochemical compounds, such as curcumin, green tea extract, resveratrol, isothiocyanates, lycopene or genistein against this malignancy. However, poor bioavailability and lack of in vivo and clinical studies and complex pharmacokinetic profiles limit their huge potential of application. However, recent nanotechnological and related advances have shown to be promising in improving the bioavailability, absorption and efficacy of such compounds.

Antiretroviral Therapy in Children and Adolescents: A Look Into Modern Single Tablet Regimens.

Single tablet regimens (STRs) have simplified antiretroviral therapy (ART) over the years in the adult human immunodeficiency virus (HIV) population. However, there is still a prevalent need to simplify regimens in children and adolescents living with HIV. Finding the optimal regimen requires a multi-factorial approach due to their complex pharmacokinetic profiles throughout childhood and the challenges and limitations of medication non-adherence in the pediatric population. These challenges include pill size, available formulations, palatability, and caregiver health literacy, which can all affect the proper administration of medications. The complexity of this population implies the importance of customizing everyone's antiretroviral regimen so that the patient and family can successfully adhere to the therapy. The current recommendations for ART in the adult and pediatric populations are similar, yet the use of STRs are limited. The goal of this review was to assess current data on available STRs and determine their utility as ART in the pediatric population.

Monoclonal antibodies for severe asthma: Pharmacokinetic profiles.

Several monoclonal antibodies (mAbs) (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) are currently approved for the treatment of severe asthma. They have complex pharmacokinetic profiles. These profiles are unique in that they are dependent on their structure as well as can be markedly influenced by the biology of their target antigen, but their general behaviour can still be considered a class property, similar to their endogenous IgG counterpart. They cannot be administered by oral route, have a slow distribution into tissue, are metabolized to peptides and amino acids in several tissues but are protected from degradation by binding to protective receptors (the FcRn), which explains their long elimination half-lives. Their clearance is nonlinear because of the saturation of the target-mediated elimination. Also anti-drug antibody (ADA) response and off-target binding, as well as their glycosylation pattern, can influence the pharmacokinetics of mAbs.

Development of a joint population pharmacokinetic model of ezetimibe and its conjugated metabolite

Ezetimibe (EZE) is an extensively used antihyperlipidemic drug with an important cholesterol lowering activity. It undergoes extensive first-pass metabolism to form its active glucuronide metabolite (EZEG). Both drugs exhibit complex pharmacokinetic profiles attributed mainly to repetitive enterohepatic kinetics. The aim of the present study was the investigation of EZE and EZEG pharmacokinetics (PK), through the development of a joint population pharmacokinetic model able to characterize their kinetic processes and enterohepatic recirculation simultaneously. Concentration-time data derived from a bioequivalence study in 28 healthy subjects were used for the analysis. Population PK modeling was performed on the obtained data using nonlinear mixed effect modeling approach, where different methodologies were applied for the description of the complex metabolism and recirculation processes of the two compounds. EZE and EZEG concentrations were best described by a population PK model incorporating first-pass metabolism and an enterohepatic recirculation loop, accounting for the recycling process of the two moieties. This is the first joint population pharmacokinetic model describing the kinetics of both EZE and EZEG.

Methadone for Analgesia in Children with Life-Limiting Illness: Experience from a Tertiary Children's Health Service.

Methadone has the potential to assist in the management of pain in children with life-limiting illness, but its use is limited by its complex pharmacokinetic profile and limited research on its use in children. This is a retrospective review of the use of methadone as an analgesic in 16 children with life-limiting illness. Efficacy, dosing and side effect profile were analysed. Fifteen (94%) patients had improvements in their analgesia with minimal observed adverse effects. Patients were either rapidly converted from a prior opioid in one change or received methadone as an adjunct medication. Conversions were calculated using ratios frequently in the range of 10:1 to 20:1 from the oral morphine equivalent total daily dose (MEDD). Adjunct initial dosing was a low dose trial, often beginning with 1 mg at night. Only two patients required a dose adjustment due to side effects attributed to methadone. This was despite the cohort having significant underlying illnesses, extensive concurrent medications, and high methadone dosing where needed. Analysis of dosing and ratios indicates that an individualised approach is required. Based on this and on the infrequency of methadone use in this population, specialist assistance with dosing is recommended. Further research, including prospective and pharmacokinetic studies, is recommended.

Assessing Vancomycin Dosing Per Pharmacy in Elderly Patients Over the Age of 74 Years

Vancomycin has a complex pharmacokinetic profile and carries potential risks for nephrotoxicity and ototoxicity. The pharmacokinetic profile in elderly patients significantly differs from that of younger patients. It is common practice in many institutions for pharmacists to intentionally round serum creatinine levels to 1 mg/dl in elderly patients with levels &lt;1 mg/dl to avoid overestimating clearance and toxicities. This can potentially lead to underestimation of creatinine clearance, and subsequently lead to vancomycin under dosing. The aim of this study was to evaluate vancomycin target trough attainment and the time to trough attainment with vancomycin dosing per pharmacy in elderly patients. Methods In this retrospective study, patients 75 years and older who received vancomycin at our institution were evaluated. Subjects were included in the study if they were at least 75 years of age, received intravenous vancomycin therapy, and had a vancomycin trough drawn after the third dose. The study patients were divided into three serum creatinine groups; &lt;0.8 mg/dl (LSCr), 0.8–0.9 mg/dl (MSCr), and ≥1 mg/dl (HSCr). Patients were excluded from the study if they did not meet inclusion criteria, had no trough levels drawn, or were &lt;75 years of age. Results Two hundred and four patients 75 years or older were included in the study. The target trough attainment was highest in the HSCr group (n = 37, 80%), which was significantly higher than the LSCr (n=21, 31%; p&lt;0.0001) and MSCr (n=42, 46%; p&lt;0.0001) groups. The time to target trough goals (days, mean ± SD) differed between the three groups, with the LSCr group taking the longest duration: LSCr: 5.14 ± 2.5; MSCr: 3.74 ± 1.1; HSCr: 3.78 ± 1.6, p=0.005. Conclusion Adjustments need to be done to improve vancomycin dosing per pharmacy in patients 75 years of age and older. This study shows that LSCr patients (&lt;0.8 mg/dl) had the lowest rates of target trough level attainment. Intentionally rounding serum creatinine to 1 mg/dl if values are less when estimating renal function in this older patient population may not be predictive of true renal function and can decrease the likelihood of target attainment or increase time to target attainment.

Cigarette smoking and heavy coffee drinking affect therapeutic response to olanzapine

Introduction/Objective. Considering relatively complex pharmacokinetic profile of olanzapine, it is expected that certain medications and some compounds, found in food and drink, can induce or inhibit its metabolism. The aim of our study was to investigate the influence of cigarette smoking and heavy coffee consumption on the clinical response to olanzapine. Methods. The phase IV, open-labeled, four-week-long prospective clinical trial included 108 adult patients diagnosed with schizophrenia. According to cigarette smoking (n = 52) and coffee drinking (n = 55), four subgroups were defined: non-smokers, non-heavy coffee consumers (group 1), non-smokers, heavy coffee consumers (group 2), smokers, non-heavy coffee consumers (group 3) and smokers and heavy coffee consumers (group 4). Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF) scales were used for therapeutic response evaluation. Results. Baseline and final GAF scores were 33.3 ? 5.0 and 61.5 ? 9.6, respectively, and PANSS scores were 100.7 ? 3.9 and 85.5 ? 5.4, respectively. The changes of GAF and PANSS scores from the baseline to the study end were 115.1 ? 35.7 and -19.6 ? 3.1, respectively (group 1), 91.1 ? 30.8 and -15.3 ? 2.9, respectively (group 2), 76.1 ? 29.8 and -13.4 ? 4.4, respectively (group 3), and 64.7 ? 29.3 and -11.3 ? 3.22, respectively (group 4), making significant subgroup differences for both scale scores (p &lt; 0.001). Cigarette smoking and heavy coffee drinking significantly and independently diminished improvement in both GAF and PANSS total score (p &lt; 0.001). Changes of body mass index from the baseline significantly influenced the change of PANSS total score only (p = n.s.), in a negative direction (r = -0.454, p &lt; 0.001). Conclusion. Smoking and heavy coffee drinking influenced effects of olanzapine in patients with schizophrenia treated in routine practice.

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting

PurposeDue to the complex pharmacokinetic profiles of phenytoin (PHT) and fosphenytoin (FOS), achieving sustained, targeted serum PHT levels in the first day of use is challenging. MethodsA population based approach was used to analyze total serum PHT (tPHT) level within 2–24h of PHT/FOS loading with or without supplementary maintenance or additional loading doses among PHT-naïve patients in the acute hospital setting. Adequate tPHT serum level was defined as ≥20μg/mL. ResultsAmong 494 patients with 545 tPHT serum levels obtained in the first 2–24h after the loading dose (LD), tPHT serum levels of either <or≥20μg/mL were observed along wide and overlapping cumulative dose ranges. Among those receiving 15–20mg/kg and 20–55mg/kg weight-based loading dose, 63% and 51% respectively did not attain tPHT serum level of ≥20μg/mL even within the first 6h of treatment. For the 393 available concomitant free and total serum PHT levels, correlation was weak, r=0.36. ConclusionClose laboratory surveillance and PHT/FOS dose adjustments are recommended to ensure adequate and sustained tPHT serum levels early in treatment. Free serum PHT level is the preferred method of drug monitoring.

Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for valproic acid and divalproex

Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (Cmax) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.

Food Effect Studies for Oncology Drug Products

Oral antineoplastic agents provide convenience to the patient, but are accompanied by challenges distinct from parenteral cancer treatment. Challenges include a more complex pharmacokinetic profile, with food influencing the absorption of many agents. Standards for evaluating and labeling prandial implications on oral chemotherapy are inconsistent; studies to determine food effects should be conducted early, and potentially often, during drug development with standardization on how rational fasting or fed recommendations are presented in the package insert (PI).

Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib: Towards Optimized Dosing.

Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies.

Evaluation of Teaching Clinical Pharmacology of Antiarrhythmic Drugs to First-Year MBBS Students Through Worksheet-Based Small-Group Discussion.

Cardiac arrhythmias are a major cause of morbidity and mortality across the world. Learning the science behind the use of antiarrhythmic drugs is essential for all medical graduates. However, many antiarrhythmic drugs are available, and most of them have complex pharmacodynamic and pharmacokinetic profiles. We tried to improvise our teaching by conducting interactive, worksheet-based, small-group discussion on antiarrhythmic drugs with preclinical students of School of Medicine, Taylor’s University, Malaysia. This survey was conducted to analyze the outcomes of worksheet-based, small-group discussion.

The Role of Metabolizing Enzymes and Transporters in Antiretroviral Therapy.

Patients with human immunodeficiency virus (HIV) receive antiretroviral therapy (ART) through the use of antiretroviral drugs. A combination of at least three drugs that suppress HIV replication is used as standard treatment, and this is often called "highly active antiretroviral therapy" (HAART). Virus resistance is less likely when three or more drugs are used. A complication of anti- HIV drugs has a complex pharmacokinetic profile which is involved with extensive metabolism and transport by drug metabolizing enzymes (e.g., CYPs, SULTs and UGTs) and transporters (e.g., ABC and SLC). Severe drug-drug interactions (DDIs) can occur with combinations of antiretroviral drugs and this can lead to treatment failure or drug-induced toxicities. Previous reviews have focused on the role of CYPs and ABC transporters with use of antiretroviral drugs and their contributions to DDIs. In this review, we systematically and comprehensively explain the roles of enzymes (including CYPs, UGTs and SULTs) and transporters (including ABC and SLC) on all antiretroviral drugs listed on the FDA's website. We also identify the DDIs that have been shown to be clinically important and associated with drug metabolism and transport alterations. Furthermore, we discuss herb-drug interactions that have been shown with long-term HAART when an herb is used to reduce side effects.

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug-Drug Interactions.

Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4h and an elimination half-life (t ½) of ≈15-20h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

Clopidogrel: A multifaceted affair.

Clopidogrel has been the therapy of choice, combined with aspirin, against platelet aggregation in patients at risk of suffering a vascular thrombotic event. Not all patients respond equally to clopidogrel, an observation that has led to searching for a test that, in the clinical setting, could predict patients' "resistance" to therapy. The evidence reveals a complex pharmacokinetic profile for clopidogrel, with multiple players involved, including cytochromes, characteristics of the target tissue, and accompanying clinical conditions. Despite FDA black box warnings recommending CYP2C19 genotyping before clopidogrel use, no robust evidence indicates that CYP2C19 function determines clinical response to the drug, either based on the presence of loss of function alleles or drug interactions with CYP2C19 inhibitors, like omeprazole. A tailored anti-aggregation treatment based on ex vivo platelet reactivity also seems unlikely due to the lack of robustness of most assays. The identification of clinical conditions that are at higher risk of new cardiovascular events, such as diabetes, obesity, coronary artery disease, or specific stenting procedures, seems to be a prudent approach to tailor anti-platelet therapy with more powerful drugs, accompanied by careful counseling to promote patient compliance.

Efficiency of individual dosage of digoxin with calculated concentration.

BackgroundDigoxin is a frequently prescribed drug, particularly in the elderly population, in which there is an increased prevalence of atrial fibrillation and cardiac failure. With its complex pharmacokinetic profile and narrow therapeutic index, use of digoxin requires regular monitoring of blood levels. Recent evidence suggests that a lower concentration range (0.4–1.0 ng/mL) is preferable in patients with congestive heart failure and a higher range (0.8–2.0 ng/mL) is needed in patients with atrial tachyarrhythmia. The Konishi equation is widely used to predict the serum digoxin concentration (SDC) in Japan. This study assessed the correlation between SDC predicted by the Konishi equation and that actually measured in Chinese patients and investigated the impact of renal function on SDC.MethodsThe study subjects comprised 72 patients with cardiac failure or/and atrial tachyarrhythmia seen at our hospital from January 2012 to December 2013. The patients were divided into five groups according to Kidney Diseases Outcome Quality Initiative guidelines. SDCs were measured using the Abbott Architect i1000 immunology analyzer. The correlations between measured SDCs and calculated SDCs and between clearance of digoxin and creatinine clearance rate were assessed retrospectively.ResultsThe correlation between measured and predicted SDC calculated by the Konishi equation was significant (r=0.655, P<0.001) for the 72 patients overall; however, correlations within the different stages of renal function were nonsignificant, with a correlation found only in patients with stage 3 (30 mL per minute < creatinine clearance <60 mL per minute). With regard to the correlation between clearance of digoxin and creatinine clearance, our results show that although there was a significant correlation between clearance of digoxin and creatinine clearance in the group overall, correlations were not evident within the different stages of renal function.ConclusionThe results of this study indicate that clearance of digoxin and the creatinine clearance rate cannot be explained by renal function alone and that the validity of the Konishi equation for individualizing the digoxin dosage in Chinese patients is limited, being applicable only in stage 3 renal disease. Further research in larger numbers of patients across all stages of renal function will be required in the future to verify the original Konishi model.

Synthesis, metabolite analysis, and in vivo evaluation of [11C]irinotecan as a novel positron emission tomography (PET) probe

Irinotecan is a semisynthetic derivative of camptothecin that exerts potent antitumor activity by inhibiting topoisomerase I. Despite much research into the complex pharmacokinetic profile and pharmacodynamic effects of irinotecan, unpredictable and severe side effects are still commonly observed. In this study, we synthesized [(11)C]irinotecan as a positron emission tomography (PET) probe, performed the metabolite analysis, and evaluated the biodistribution and kinetics of [(11)C]irinotecan using small animal PET. [(11)C]Irinotecan was synthesized by two routes using [(11)C]phosgene and [(11)C]carbon dioxide fixation. Metabolites in the plasma of mice following injection of [(11)C] irinotecan were investigated using a combination of column-switching high-performance liquid chromatography (HPLC) and on-line solid-phase extraction (SPE). Whole-body PET studies were conducted in wild-type mice and P-glycoprotein and breast cancer resistance protein (Pgp/Bcrp) knockout mice. [(11)C]Irinotecan was successfully synthesized by the two abovementioned routes. Decay-corrected radiochemical yields based on [(11)C]carbon dioxide using [(11)C]phosgene and [(11)C]carbon dioxide fixation were 8.8 ± 2.0% (n=8) and 16.9 ± 2.9 % (n=5), respectively. Metabolite analysis of the plasma of mice following injection of [(11)C]irinotecan was successfully performed using the column-switching HPLC and on-line SPE combination resulting in greater than 87 % recovery of radioactivity from HPLC. In the PET study in mice, the radioactivity levels in the brain, liver, and small intestine were slightly increased by inhibition of the Pgp/Bcrp function for more than 30 min after [(11)C]irinotecan injection. This result demonstrated that in vivo behavior of [(11)C] irinotecan and radioactive metabolites are influenced by the Pgp/Bcrp function. PET studies using [(11)C]irinotecan combined with metabolite analysis may be a useful tool for evaluating irinotecan pharmacokinetics and toxicity.