Individual Differences In Pharmacokinetics Research Articles

Antibiotics-Induced Depletion of Rat Microbiota Induces Changes in the Expression of Host Drug-Processing Genes and Pharmacokinetic Behaviors of CYPs Probe Drugs.

The metabolism of exogenous substances is affected by the gut microbiota, and the relationship between them has become a hot topic. However, the mechanisms by which the microbiota regulates drug metabolism have not been clearly defined. This study characterizes the expression profiles of host drug-processing genes (DPGs) in antibiotics-treated rats by using an unbias quantitative RNA-sequencing method and investigates the effects of antibiotics-induced depletion of rat microbiota on the pharmacokinetic behaviors of cytochrome P450s (CYPs) probe drugs, and bile acids metabolism by ultra-performance liquid chromatography-tandem mass spectrometry. Our results show that antibiotics treatments altered the mRNA expressions of 112 DPGs in the liver and jejunum of rats. The mRNA levels of CYP2A1, CYP2C11, CYP2C13, CYP2D, CYP2E1, and CYP3A of CYP family members were significantly downregulated in antibiotics-treated rats. Furthermore, antibiotics treatments also resulted in a significant decrease in the protein expressions and enzyme activities of CYP3A1 and CYP2E1 in rat liver. Pharmacokinetic results showed that, except for tolbutamide, antibiotics treatments significantly altered the pharmacokinetic behaviors of phenacetin, omeprazole, metoprolol, chlorzoxazone, and midazolam. In conclusion, the presence of stable, complex, and diverse gut microbiota plays a significant role in regulating the expression of host DPGs, which could contribute to some individual differences in pharmacokinetics. SIGNIFICANCE STATEMENT: This study investigated how the depletion of rat microbiota by antibiotics treatments influences the expression profiles of host DPGs and the pharmacokinetic behaviors of CYPs probe drugs. Combined with previous studies in germ-free mice, this study will improve the understanding of the role of gut microbiota in drug metabolism and contribute to the understanding of individual differences in the pharmacokinetics of some drugs.

Research Progress in Concentration Monitoring of Antipsychotic Drugs

Objective: To explore the drug concentration detection of antipsychotic drugs in the treatment of schizophrenia and other psychiatric diseases. Methods: Collecting the research results of relevant references in recent years, and summarizing the development and existing problems of the detection of psychotropic drugs in recent years from the perspective of drug detection methods, multidisciplinary integration, and interdisciplinary cooperation, so as to provide a reference for the follow-up monitoring of antipsychotic drugs. Results: It was found that the individual differences in pharmacokinetics of these drugs were large, and the side effects and toxic reactions were not easily distinguished from the aggravation of the symptoms of the disease itself. Conclusion: Through the analysis of the collected literature, we can understand the research progress of antipsychotic drug concentration monitoring, and provide strong evidence for the realization of clinical individualized precise treatment.

Influence of CYP3A4*22 and CYP3A5*3 combined genotypes on tacrolimus dose requirements in Egyptian renal transplant patients.

Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A4*22 and CYP3A5*3 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A4*22 and CYP3A5*3 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients. This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups. The CYP3A4*22 allele was rare (3.2% of subjects) while the CYP3A5*3 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A4*22 carriers than CYP3A4*1/*1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p= 0.028). Patients harbouring the one copy of the CYP3A4*22 allele and the CYP3A5*3/*3 genotype (n= 5) were classified as poor tacrolimus metabolizers, the CYP3A5*3/*3 plus CYP3A4*1/*1 genotype as intermediate metabolizers (n= 60), and the CYP3A4*1/*1 plus CYP3A5*1/*1 genotype as normal metabolizers (n= 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p< 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes. Pharmacogenetics testing for CYP3A4*22 and CYP3A5*3 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.

A personalized limited sampling approach to better estimate terminal half‐life of FVIII concentrates

IntroductionHemophilia A is a bleeding disorder characterized by a deficiency of a coagulation factor VIII and optimally treated using pharmacokinetics (PK)‐guided prophylactic replacement therapy. To decrease patient burden, PK can be estimated from sparse sampling leveraging population PK modeling. However, recommendations for sampling times meant for patients with hemophilia A as a group may not be optimal at the individual level. ObjectiveTo evaluate a personalized limited sampling approach (Personalized LSA) that suggests a next sampling time point that would provide a more accurate estimation of terminal half‐life of FVIII concentrates when using a population PK approach. Methods331 PK studies with rich sampling were extracted from the WAPPS‐Hemo database. Two sampling approaches were evaluated and compared: 974 PK studies consisting of two samples were built from the rich sampling data including one sample selected using the personalized LSA prediction; 974 PK studies consisting of two samples were built from the rich sampling data including one sample selected randomly. Half‐life values were estimated on the sparse data and compared within patients to the estimates obtained on the rich data for assessing the error on half‐life values. ResultsRelative errors between estimates from sparse sampling data using personalized LSA and from rich sampling data were always lower than 20% and significantly lower than the comparative approach that used random sampling (median–95th percentile were 3.8%–13.1% vs. 7.0%–23.5%, respectively, p‐value < 10−10). Moreover, less than 4% of the samples suggested by the personalized LSA were below the limit of quantification. ConclusionsIdentifying the most informative sampling points for PK assessment using a Personalized LSA approach that accounts for individual differences in PK improves the precision of FVIII terminal half‐life estimates in sparse sampling.

Distribution evaluation of tacrolimus in the ascitic fluid of liver transplant recipients with liver cirrhosis by a sensitive ultra-performance liquid chromatography-tandem mass spectrometry method.

Tacrolimus has a narrow therapeutic index and large individual differences in pharmacokinetics. The distribution of tacrolimus in ascitic fluid and its influence on whole-blood tacrolimus were unclear. In this study, a sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was established and validated for the quantification of tacrolimus in the ascitic fluid of liver transplant recipients. Chromatographic separation was achieved on an Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column (2.1 × 100mm, 3.5 μm). Mass spectrometry was performed in multiple reaction monitoring conditions of transitions m/z 821.4→768.5 for tacrolimus. The concentrations of tacrolimus in the ascitic fluid range from 0.2 to 3.0ng/mL, accounting for 1.19-31.87% of whole-blood tacrolimus concentrations. A linear mixed model showed a statistically significant positive correlation between the steady-state trough blood concentration of tacrolimus and the corresponding amount of tacrolimus excreted in the ascitic fluid for 24 consecutive hours, especially after normalization by daily dose per unit body weight. These data suggested that the distribution of tacrolimus in the ascitic fluid has great individual differences. The whole-blood tacrolimus concentration, dose per unit body weight, and other confounding factors may contribute to the excretion of tacrolimus in ascitic fluid, but the influence of tacrolimus excretion in drained ascitic fluid on the whole-blood tacrolimus concentration is negligible.

Population pharmacokinetics and pharmacodynamics of fondaparinux inJapanese patients after artificial total kneereplacement .

This study was designed to clarify the factors affecting the efficacy, adverse events, and pharmacokinetics of fondaparinux in Japanese patients undergoing artificial knee replacement surgery. Fondaparinux (1.5mg/d) was administered subcutaneously to patients (n=30) at 24hours after surgery, and blood samples were taken at various time points thereafter. Venous thromboembolism (VTE), presence of bleeding, and pharmacokinetics were evaluated. Multivariate analysis and population pharmacokinetic analysis were performed to detect factors that necessitated withdrawal of fondaparinux and individual differences in its pharmacokinetics. VTE was observed in 9 patients (3 for whom administration was continued and 6 for whom withdrawal was necessary). The maximum plasma concentration of fondaparinux was found to be a significant factor determining withdrawal of the drug. Population pharmacokinetic analysis demonstrated that individual renal function and body weight were significant factors associated with apparent clearance and volume of distribution, respectively. A high maximum plasma concentration of fondaparinux may result in subcutaneous hemorrhage, necessitating withdrawal of fondaparinux administration. The patient's kidney function and body weight also contribute to individual differences in pharmacokinetics. We recommend considering an adjustment to the dose of fondaparinux based on body weight in patients undergoing artificial knee replacement surgery. .

Faster alcohol metabolism is associated with increased stimulation and within session consumption.

Variability in subjective response (SR) to alcohol predicts drinking and the development of Alcohol Use Disorders (AUDs). Although both alcohol pharmacokinetics (i.e., absorption and metabolism) and SR are impacted by aspects of the drinking situation (e.g., rate of consumption), relations between individual differences in pharmacokinetics and SR have received little attention. The current study examined the extent to which alcohol pharmacokinetics impact SR and drinking during a single alcohol administration session. A total of 119 (67% male) social drinkers were administered a dose of alcohol with a target blood alcohol concentration (BAC) of 0.08g%. The Biphasic Alcohol Effects Scale was administered twice at matched ascending and descending limb BACs following alcohol consumption to assess SR. Pharmacokinetic properties (absorption and metabolism) were inferred using multiple BAC readings to calculate the area under the curve during the ascending limb (absorption) and descending limb (metabolism). Following completion of SR measures, an ad libitum taste rating task utilizing nonalcoholic beer was implemented to assess voluntary 'alcohol' consumption. Results indicated that participants who metabolized alcohol more quickly maintained a greater level of subjective stimulation on the descending limb. Faster metabolism was indirectly related to ad lib nonalcoholic beer consumption through greater maintenance of stimulant effects. Absorption did not significantly predict SR or within session drinking. The results increase understanding of SR variability and suggest that heightened stimulation that is sustained across limbs of the BAC curve may increase risk for excessive consumption. Individual differences in alcohol metabolism may be an identifiable biomarker of this high risk pattern of SR. (PsycINFO Database Record

Role of Drug Metabolic Enzymes and Transporters in Drug-Drug Interactions Between Antiretroviral and Antituberculosis Drugs

Drug-drug interactions is one of the major determinant in drug development and clinical applications. Individual differences in pharmacokinetics may cause extensive variability in drug efficacy, toxicity and adverse drug reactions, and represent a major concern in drug development. According to world health organization, an estimated 1.2 million patients were diagnosed with HIV/TB coinfection in 2015, and approximately 400,000 coinfected individuals were died in 2016. During treatment of tuberculosis and human immunodeficiency virus (HIV) coinfections, a combination of multiple therapeutic drugs is used, which is potential for interactions between coadministered drugs. Drug metabolizing enzymes and transporters plays vital role in the disposition, pharmacokinetics as well as efficacy and toxicity of many antituberculosis (anti-TB) and antiretroviral (ARVs) drugs. The current understanding of drug-drug interactions involving the first-line antituberculosis and antiretroviral (ARVs) drugs are reviewed and summarized in this article emphasizing the role of drug transporters and metabolic enzymes. It is found that several clinical drug-interactions are caused by the phase I and II metabolic enzymes (cytochrome-P-450s, CYPs, UDP-glucuronosyltransferases, UGTs) and uptake/ efflux transporters, particularly permeability glycoprotein, brest cancer resistance protein, multidrug resistance protein and solute carrier transporters). Overall, this study will be helpful to understand the drug-interactions between the ARV or anti-TB drug regimen or with concomitantly used drugs at a glance. By understanding the unique functions and characteristics of enzymes and transporters, it may use in the management of drug interactions in the treatment of HIV and TB. Keywords: Drug-drug interactions, Metabolic Enzymes, Membrane Transporters, Antiretroviral and antituberculosis drugs

Pooled bioequivalence study database from Turkey: characterization of adverse events and determination of split points based on Gini Index as a promising method.

BackgroundManufacturing of and medication with generic drugs is increasing around the world. Bioequivalence (BE) studies are being performed routinely by Contract Research Organisations (CROs) in Turkey. However, an overall evaluation for the attended volunteers, examined Active Pharmaceutical Ingredients (APIs) and the observed adverse events have not been studied in the field.ObjectiveOur aim was to revisit and compile the BE studies carried out between the years 2000–2013 of a CRO (N-CRO) in Turkey.MethodsA dataset of 261 BE studies has been created for the observed adverse events with regards to the frequency, type, and drug subgroups. As an advanced evaluation, the Gini Index method has been used in the 63 available BE studies to obtain split points for two pharmacokinetic parameters, area under the plasma/serum concentration (AUC) and maximum plasma/serum concentration (Cmax), in order to investigate their likely effect on the adverse events.ResultsThousand six hundred and forty two adverse events were found in the 261 BE studies involving 7828 volunteers with the frequency of 6.29 per study and 0.21 per volunteer. The most frequently observed adverse events were; headache, somnolence, nausea, dizziness and vomiting, respectively. Hundred and nine different APIs were observed. ‘Genitourinary system and sex hormones’ subgroup drugs had the highest frequency of the adverse events. Adverse event frequencies above the identified split points for Cmax and AUC values were higher than the frequencies below them.ConclusionThe review of 13 years period of BE studies revealed that the demographic properties of the volunteers and the study designs were in compliance with national and international guidelines. The promising outcome could be showing the increase of the adverse event frequencies above the obtained split points as the reflection of the likely individual pharmacokinetic differences in the adverse event occurence.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2527-4) contains supplementary material, which is available to authorized users.

Pharmacokinetics-Based Individualized Dosing Strategy to Predict Maximum Tolerated Dose of Hydroxyurea in Children with Sickle Cell Anemia

▪Background: Hydroxyurea is the primary disease-modifying therapy for adults and children with sickle cell anemia (SCA). Recent NHLBI guidelines include a recommendation for expanded hydroxyurea use, particularly for young children. The laboratory and clinical benefits of hydroxyurea therapy are optimized when escalated to maximum tolerated dose (MTD), but the process of dose escalation requires expertise and frequent laboratory tests. The time to reach MTD using traditional empirical escalation usually takes >6 months, which can delay the laboratory and clinical benefits. In addition, all children with good adherence at MTD will respond to hydroxyurea, but with substantial interpatient variability in both the MTD itself and the %HbF levels achieved, suggesting important individual differences in pharmacokinetics (PK) that contribute to this phenotypic variability.Objective: The primary objective of this study was to develop an individualized Bayesian adaptive dosing strategy to reduce the time required to reach hydroxyurea MTD for children with SCA. Achieving this objective required the development of a population PK model and identification of the most informative sampling times for Bayesian estimation order to reduce the number of observations required for robust estimation of hydroxyurea PK parameters for individual patients.Methods: PK data at baseline from 96 children with SCA enrolled in the prospective Hydroxyurea Study of Long-term Effects (HUSTLE, NCT00305175) were used to develop a population PK model using nonlinear mixed effects modeling (NONMEM 7.2). Patient demographics and clinical chemistry measurements were included for covariate analyses. The final model was validated by bootstrap analysis and visual predictive check. To identify the optimal sampling times and number of samples required to robustly estimate individual PK parameters and total hydroxyurea exposure (AUC), a D-optimal design analysis was performed using the final PK model with constraints of clinical feasibility.Results: Hydroxyurea PK profiles were best described by a one compartment model with Michaelis Menten elimination and a transit absorption model. Hydroxyurea serum concentrations showed substantial interpatient variability with AUC on Day 1 ranging from 40.0 to 149.2 mg*h/L. The average AUC at MTD (mean ± SD) was 115.7 ± 34.0 mg*h/L, so this value was chosen as the target hydroxyurea AUC for the final PK model-based approach. Of the tested covariates, body weight and cystatin C were identified as significant predictors of hydroxyurea clearance, but neither serum creatinine nor estimated creatinine clearance was identified as predictors of hydroxyurea clearance. D-optimal design indicated that three serum concentrations collected at 15-20 minutes, 50-60 minutes, and 3 hours after oral administration would accurately estimate systemic hydroxyurea exposure. Figure 1 demonstrates an example from a patient, demonstrating the PK profile obtained using the sparse sampling technique (Panel A) and the modeling to predict a dose that would target a AUC of 115 mg*h/L (Panel B).Conclusions: We have established a PK model-based individualized dosing strategy to predict hydroxyurea MTD in children with SCA. Our selective sampling strategy requires only three serum samples to be collected over 3 hours and is therefore more feasible and practical, particularly for very young children, than traditional hydroxyurea PK analysis that requires frequent blood collections over 6-8 hours. This novel Bayesian approach is being prospectively evaluated in the Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). In TREAT, hydroxyurea concentrations are measured using HPLC after a single oral dose of 20 mg/kg, requiring only 3 fingerstick blood samples over 3 hours for accurate assessment of each patient's unique hydroxyurea PK profile. The predicted MTD is then calculated based on the amount of drug required to meet the target AUC. This strategy has the potential to individualize therapy and optimize the dose titration of hydroxyurea therapy for children with SCA, such that the laboratory and clinical benefits at MTD are achieved more quickly. [Display omitted] DisclosuresOff Label Use: Hydroxyurea is not FDA-approved for children with sickle cell anemia. Ware:Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding; Eli Lilly: Other: DSMB membership; Bayer Pharmaceuticals: Consultancy.

A Pharmacometabonomic Approach To Predicting Metabolic Phenotypes and Pharmacokinetic Parameters of Atorvastatin in Healthy Volunteers.

Genetic polymorphism and environment each influence individual variability in drug metabolism and disposition. It is preferable to predict such variability, which may affect drug efficacy and toxicity, before drug administration. We examined individual differences in the pharmacokinetics of atorvastatin by applying gas chromatography-mass spectrometry-based metabolic profiling to predose plasma samples from 48 healthy volunteers. We determined the level of atorvastatin in plasma using liquid chromatography-tandem mass spectrometry. With the endogenous molecules, which showed a good correlation with pharmacokinetic parameters, a refined partial least-squares model was calculated based on predose data from a training set of 36 individuals and exhibited good predictive capability for the other 12 individuals in the prediction set. In addition, the model was successfully used to predictively classify individual pharmacokinetic responses into subgroups. Metabolites such as tryptophan, alanine, arachidonic acid, 2-hydroxybutyric acid, cholesterol, and isoleucine were indicated as candidate markers for predicting by showing better predictive capability for explaining individual differences than a conventional physiological index. These results suggest that a pharmacometabonomic approach offers the potential to predict individual differences in pharmacokinetics and therefore to facilitate individualized drug therapy.

Comparison of once-daily versus twice-daily combination of Ropinirole prolonged release in Parkinson’s disease

BackgroundRopinirole prolonged release (RPR) is a once-daily formulation. However, there may be individual pharmacokinetic differences so that multiple dosing may be preferred in some individuals. This study compares once-daily and twice-daily RPR in patients with Parkinson’s disease.MethodsThis study was an open-label crossover study. We enrolled Parkinson’s disease patients on dopamine agonist therapy with unsatisfactory control such as motor fluctuation, dyskinesia and sleep-related problems. Agonists were switched into equivalent dose of RPR. Subjects were consecutively enrolled into either once-daily first or twice-daily first groups, and received the same amount of RPR in a single and two divided dosing for 8 weeks respectively in a crossover manner without a washout period.The primary outcome was a questionnaire of the preference completed by patients in the last visit. The secondary outcome measures included the Unified Parkinson’s Disease Rating Scale part 3 (mUPDRS), Hoehn and Yahr stage (H&Y); sleep questionnaire including overall quality of sleep, nocturnal off symptoms and early morning symptoms; Epworth Sleep Scale (ESS); compliances and patient global impression (PGI).ResultsA total of 82 patients were enrolled and 61 completed the study. 31 patients preferred twice-daily regimen, 17 preferred the once-daily regimen, and 13 had no preference. Their mean mUPDRS, H&Y, ESS, sleep quality, compliance and adverse events were not statistically different in both regimens. PGI-improvement on wearing off defined was better in twice-daily dosing regimen.ConclusionsRPR is a once-daily formulation, but multiple dosing was preferred in many patients. Multiple dosing of RPR might be a therapeutic option if once-daily dosing is unsatisfactory.Trial registrationThis study is registered with ClinicalTrials.gov, number NCT00986245.

CYP3A and ABCB1 Genetic Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Tacrolimus and Its Metabolites (M-I and M-III)

We prospectively studied renal transplant recipients receiving tacrolimus to determine the relationship between the CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms and the pharmacokinetics (PK) and pharmacodynamics (PD) of tacrolimus and its metabolites. Renal transplant recipients receiving tacrolimus were genotyped for CYP3A4*4, CYP3A4*5, CYP3A4*18, CYP3A5*3, ABCB1 c.1236C→T, ABCB1 c.2677G→A/T, and ABCB1 c.3435C→T. Dose-adjusted trough concentration (C0) of tacrolimus and its metabolites (M-I and M-III) and PK and PD (T-cell and monocyte subsets) were determined on transplantation days -2, 5, 30, and 90 and correlated with the corresponding genotypes. The dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12 were significantly higher and the mean fluorescence intensity (MFI) of HLA/DR in monocytes was significantly lower in patients with CYP3A5*3/*3 than in patients with CYP3A5*1/*1 or CYP3A5*1/*3. However, there was no significant difference in the dose-adjusted C0 of tacrolimus and its metabolites, PK and PD among the ABCB1 genotypes. The MFI of HLA/DR in monocytes showed a significant negative correlation with dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12. In a multiple regression analysis, the presence of the CYP3A5*3/*3 genotype was a significant independent variable determining the dose-adjusted C0 of tacrolimus and its metabolites, AUC0-12, and the MFI of HLA/DR in monocytes. This study demonstrates that the CYP3A5 genetic polymorphisms are associated with the individual differences in PK and PD as well as in C0 of tacrolimus and its metabolites. The MFI of HLA/DR in monocytes might be considered to be a significant tool for monitoring tacrolimus efficacy.

Consumption of a High-Fat Diet during Pregnancy Changes the Expression of Cytochrome P450 in the Livers of Infant Male Mice

It has been recently reported that the consumption of a high-fat diet during pregnancy exerts various effects on fetuses and newborn mice. The purpose of this study was to determine the effects of a high-fat diet during pregnancy on the expression of cytochrome P450 (CYP) in the livers of offspring. Mouse dams were fed a high-fat diet during pregnancy from the time of conception. After their birth, the newborn mice were fed a normal diet until 12 weeks of age. In the livers of the infant male mice that consumed a high-fat diet, the protein expression of CYP3A and CYP2C was decreased, and the protein expression of CYP1A and CYP2E was increased at 6 and 12 weeks of age. However, almost no changes were observed in the CYP proteins at 6 and 12 weeks of age in the livers of the infant female mice that consumed a high-fat diet. The amount of pregnane X receptor (PXR) translocated into the nucleus was reduced in the livers of infant male mice that consumed a high-fat diet. However, there was neither an increase in tumor necrosis factor-α or interleukin-1β nor a decrease in lithocholic acid. These data suggested that CYP3A and CYP2C might decrease as a result of the decrease in the amount of nuclear PXR in infant male mice that consumed a high-fat diet. The results of this study suggested that the consumption of a high-fat diet by pregnant mothers may be one explanation for individual differences in pharmacokinetics.

Temporal delays and individual variation in antidiuretic response to desmopressin

This study aimed to estimate the relationship between pharmacokinetics and the antidiuretic effect of desmopressin. In the investigator-blind, randomized, parallel group study, 5 dose groups and 1 placebo group, each consisting of 12 healthy, overhydrated, nonsmoking male subjects 18-55 yr of age were infused intravenously over 2 h with placebo or 30, 60, 125, 250, and 500 ng desmopressin in 50 ml of normal saline. Plasma desmopressin and urine osmolality rose by variable amounts during the infusions of 60, 125, 250, and 500 ng desmopressin. Plotting mean urine osmolality against the concurrent mean plasma desmopressin yielded a temporal delay between pharmacokinetic (PK) and -dynamic (PD) responses in all dose groups. Using simulation from the indirect-response model, assuming a constant (4 ng/ml) desmopressin concentration, this delay between PK and PD was estimated at 4 h (10th-90th percentile: 1.8-8.1). Within each group, however, there were large individual variations (2- to 10-fold) in the magnitude and duration of the antidiuretic effect. The antidiuretic effect of intravenous desmopressin in water-loaded healthy adults varies considerably due largely to factors other than individual differences in pharmacokinetics. The antidiuretic effect is time as well as dose dependent and may be self-amplifying. The most likely explanation for these findings is that the time required for a given level of plasma desmopressin to exert its maximum antidiuretic effect varies markedly from person to person due to individual differences in the kinetics of one or more of the intracellular mechanisms that promote the reabsorption of solute-free water by principal cells in renal collecting tubules.

Acute lorazepam effects on neurocognitive performance

A double-blind, placebo-controlled, crossover design was employed to determine whether acute lorazepam (2mg orally) cognitive side effects would emerge in a differential age-dependent fashion in 15 young (mean age=22years) and 12 older (mean age=64years) subjects. Acute use of lorazepam is frequently the initial treatment choice for convulsive status epilepticus or repetitive seizure clusters. Cognitive assessment was performed during drug and placebo conditions using a computerized battery of cognitive tests. With the exception of performance on the reasoning composite score, significant drug effects were present on all primary cognitive domain measures. However, the only significant drug‐by‐age interaction effect was seen for dual‐task performance. The relationship between test performance and plasma lorazepam concentrations was generally modest and non-significant, suggesting that individual differences in pharmacokinetics are not a major factor contributing to the emergence of cognitive side effects. Despite robust lorazepam effects on multiple measures of neurocognitive function, differential age effects are largely restricted to dual‐task performance. These results indicate that with the exception of dual‐task performance, older individuals in the age range of this study do not appear to be at increased risk for the emergence of cognitive side effects following a single 2‐mg dose of lorazepam.

Consumption of a high-fat diet during pregnancy decreases the activity of cytochrome P450 3a in the livers of offspring

Recent studies have reported that a high-fat diet during pregnancy exerts various effects on the foetus and newborn. The purpose of this study was to clarify the effects of a high-fat diet during pregnancy on the activity of hepatic cytochrome P450 (Cyp) 3a in offspring in mice. The protein expression level and activity of Cyp3a in the livers of 6-week-old mice born to mothers that were given a high-fat diet during pregnancy (HF group) decreased significantly compared with the Control group. Triazolam, which is a substrate of Cyp3a, was intraperitoneally administered to the mice in the HF group. Compared with the Control group, an increase in the area under the plasma concentration–time curve and a decrease in total clearance were observed in the HF group. The hepatic constitutive androstane receptor (CAR) mRNA expression level in the HF group was significantly lower than that in the Control group. An increase in phosphorylation of extracellular signal-regulated kinase (ERK) was also observed in the HF group. The results of this study revealed that a high-fat diet during pregnancy causes an increase in ERK phosphorylation and a decrease in the expression level of CAR in the livers of offspring, which leads to decreased Cyp3a expression and activity. The results suggest that individual differences in pharmacokinetics may not only be expressed by genetic predisposition but also by a mother’s living environment during pregnancy.

Individual Differences in The Pharmacokinetics of Clozapine in Healthy Chinese Adults

ABSTRACTIntroduction: Differences in response to clozapine among patients have received considerable attention. Individual pharmacokinetic differences are a major reason.Objective: The aim of this study was to investigate the pharmacokinetic variability in the blood levels of clozapine among young, healthy, Chinese male volunteers.Methods: A total of 18 volunteers who received 12.5mg of clozapine participated in the study. Blood samples were measured by using High-Performance Liquid Chromatography-Electrospray ionization tandem mass spectrometry (LC-MS/MS). The major pharmacokinetic parameters were calculated from the plasma concentration-time curve and individual variability was assessed.Results: The findings indicated that the AUC0-48h, Cmax and t1/2 varied 2.9, 2.6, and 2.0 fold, respectively among the individuals even with similar physiological status.Conclusions: Individual differences were obvious among healthy volunteers and greater differences could have been observed if more subjects had been inc...

Different Transport Activity of Human Triallelic MDR1893Ala/Ser/Thr Variant and its Association with Herb Extracts

Individual pharmacokinetic differences for herb-drug interaction have been associated with genetic variations of the multidrug resistance (MDR) gene. A high level expression of MDR protein increases cellular efflux and might decrease drug sensitivity. This study investigated the drug efflux activity difference of human MDR1 triallelic variant 2677G/T/A (rs2032582), as a nonsynonymous 893Ala/Ser/Thr, using Xenopus laevis oocytes and MDR1 overexpressing LLC-PK1 cells. Two MDR1 variants (2667T/893Ser and 2667A/893Thr) were generated using human MDR1 cDNA (2677G/893Ala). No significant difference in the expression of MDR1 893Ala/Ser/Thr was found in X. laevis oocytes. However, the MDR1 2667A/893Thr variant interestingly showed a significant decrease of efflux activity for both digoxin and daunorubicin compared with those of 893Ala and 893Ser variants. In further investigation assessing the inhibitory effects of three herbal extracts on MDR1, 893Ala and 893Ser showed significant decreases of efflux activities in treatments with P. cocos (p = 0.005 for 893Ser) and D. dasycarpus (p = 0.0009 for 893Ala; p = 0.002 for 893Ser) in X. laevis oocytes. The results in this study suggest that herbal medicines could interact with other drugs and change the therapeutic effects depending on the genetic polymorphisms of individuals.

Individual Differences in Pharmacokinetics and Pharmacodynamics of Anesthetic Agent Propofol with Regard to CYP2B6 and UGT1A9 Genotype and Patient Age

Propofol (2,6-diisopropylphenol) is administered intravenously for induction and maintenance of anesthesia; however, cases of progressive myocardial failure (propofol syndrome) related to the use of propofol have been reported. In the present study, the individual differences in pharmacokinetics and/or pharmacodynamics of propofol were investigated in patients who were genotyped for CYP2B6 and UGT1A9. Fifty-one patients treated with propofol in St. Marianna University Hospital were recruited for this study and provided written informed consent. The following parameters were analyzed: awakening time as a pharmacodynamic parameter, duration of propofol infusion, drug concentration in plasma after treatment, genotypes of CYP2B6 and UGT1A9, and age (42-84 years, mean of 65 years). Propofol was rapidly cleared from the blood of the subjects as a result of distribution and elimination. The awakening time after stopping propofol infusion was significantly correlated with the duration of infusion and the maximum concentration of propofol in these subjects. The maximum plasma concentration of propofol after normalizing with the duration of infusion was affected by the CYP2B6 G516T variant (related to impaired function) and was significantly affected by a propofol risk index score that incorporated CYP2B6 G516T and UGT1A9 I399C>T (high expression) genotypes and advanced age. These results provide important information indicating that the genotypes of the two enzymes studied and advanced age are combinative determinant factors of the pharmacokinetics and/or pharmacodynamics of propofol.