Gut microbiota-mediated metabolism of Panax notoginseng saponins and its role in pharmacokinetics and pharmacodynamics

Panax notoginseng saponins(PNS)are a class of effective ingredients in Notoginseng Radix et Rhizoma,a well-known herbal medicine called San-Qi in Chinese.After oral administration,PNS inevitably interacts with gut microbiota,and thus affect the pharmacokinetic profiles and pharmacological effects.To date,studies concering gut microbiota-mediated metabolism of PNS have not been reviewed systematically.Herein,we outline the metabolic profiles of Panax notoginseng saponins mediated by gut microbiota,as well as its role in the pharmacokinetics and pharmacodynamics on the basis of reported data.The metabolic pathways of primary saponins are proposed,and step-by-step deglycosylation is found to be the primary degradation pathways of PNS mediated by gut microbiota.Specific microorganisms and enzymes involved in the metabolic processes were summarized.Gut microbiota is deeply involved in the metabolism of PNS,affects the pharmacokinetic profiles,and produces a series of active metabolites.These metabolites were documented to play an essential role in the efficacy of the parent compounds.Future studies should focus on strengthening the real-world evidence,defining the interaction between gut microbiota and PNS,and developing the strategy for modulating gut microbiota to enhance the bioavailability and efficacy of PNS.These information would be useful for further research and clinical application of PNS.

Propofol Target-Controlled Infusion Modeling in Rabbits:Pharmacokinetic and Pharmacodynamic Analysis

This study aimed to establish a new propofol target-controlled infusion（TCI） model in animals so as to study the general anesthetic mechanism at multi-levels in vivo. Twenty Japanese white rabbits were enrolled and propofol（10 mg/kg） was administrated intravenously. Artery blood samples were collected at various time points after injection, and plasma concentrations of propofol were measured. Pharmacokinetic modeling was performed using Win Nonlin software. Propofol TCI within the acquired parameters integrated was conducted to achieve different anesthetic depths in rabbits, monitored by narcotrend. The pharmacodynamics was analyzed using a sigmoidal inhibitory maximal effect model for narcotrend index（NI） versus effect-site concentration. The results showed the pharmacokinetics of propofol in Japanese white rabbits was best described by a two-compartment model. The target plasma concentrations of propofol required at light anesthetic depth was 9.77±0.23 μg/m L, while 12.52±0.69 μg/m L at deep anesthetic depth. NI was 76.17±4.25 at light anesthetic depth, while 27.41±5.77 at deep anesthetic depth. The effect-site elimination rate constant（ke0） was 0.263/min, and the propofol dose required to achieve a 50% decrease in the NI value from baseline was 11.19 μg/m L（95% CI, 10.25–13.67）. Our results established a new propofol TCI animal model and proved the model controlled the anesthetic depth accurately and stably in rabbits. The study provides a powerful method for exploring general anesthetic mechanisms at different anesthetic depths in vivo.

Pharmacokinetic-Pharmacodynamic modeling of the analgesic effect of bupredermTM, in mice

Purpose: BupredermTM-Buprenorphine transdermal delivery system (BTDS) was developed for the treatment of post-operative and chronic pains. This study examined the relationship between the plasma concentration of buprenorphine and its analgesic effect (tail flick test) in order to assess the usefulness of pharmacokinetic-pharmacodynamic (PK-PD) modeling in describing this relationship. Methods: After patch application, plasma concentrations of bu- prenorphine in mice were measured for 72 hours with a validated LC/MS/MS system, and the analgesic effects were assessed by tail flick test for the period of 24 hours. A modified two- compartment open model was used to explain the PK properties of BTDS, and the PD model was characterized by slow receptor binding. Results: The peak buprenorphine level in plasma was achieved at 1-24 h and the effective therapeutic drug concentration was maintained for 72 hours. BupredermTM induced prolongation of tail-flick latency in a dose and time dependent manner. Maximum analgesic effect was attained at 3-6 h and was maintained for 24 h after patch application. Counter-clockwise hysteresis between the plasma concentration and the analgesic efficacy of BTDS was observed after BupredermTM application, indicating there was a delay between plasma concentrations and the effect observed. From the developed PK-PD model, Kd values (0.69-0.82 nM) that were derived from the pharmacodynamic parameters (Kon and Koff) are similar to the reported values (Kd = 0.76 ± 0.14 nM). Good agreement between the predicted and observed values was noted for the rate of change in analgesic effect data (R2 = 0.822, 0.852 and 0.774 for 0.24, 0.8 and 2.4 mg/patch, respectively). Conclusions: The established PK- PD model successfully described the relationship between plasma concentration of buprenorphine and its analgesic efficacy measured by the tail flick test. Our model might be useful in estimation and prediction of onset, magnitude and time course of concentration and pharmacological effects of BTDS and will be useful to simulate PK-PD profiles with clinical regimens.

Mechanism Based Pharmacokinetic Pharmacodynamic Modeling of Vildagliptin as an Add-on to Metformin for Subjects with Type 2 Diabetes

Various drugs are used to maintain normoglycemia in subjects with type 2 diabetes mellitus.The combination of the drugs from different classes in one single tablet may enhance the effectiveness of the anti-diabetic drugs.To investigate the impact of combining drugs on the glucose regulation of subjects with type 2 diabetes,we propose a pharmacokinetic/pharmacodynamics(PK/PD)mathematical modeling approach for a combination of metformin and vildagliptin drugs.In the proposed modeling approach,two separate PK models representing oral administration of metformin and vildagliptin for diabetic subjects are interconnected to a PD model comprising a detailed compartmental physiological model representing the regulatory effect of insulin,incretins and glucagon hormones on glucose concentration in a human body.The impact of doses of individual drugs and their combination on the blood glucose concentration of a group of type 2 diabetic subjects is investigated.It is indicated that while administration of individual drugs reduces the blood glucose levels,since they have separate mechanisms of action,combining them synergizes lowering the blood glucose levels.

Population Pharmacokinetic Pharmacodynamic Modeling of Caffeine Using Visual Analogue Scales

Caffeine is a commonly ingested psychoactive substance which affects alertness and cognition. A clinical study was conducted to determine the effect of orally ingested caffeine on visual analogue scale (VAS) responses in healthy, moderate caffeine-consuming volunteers through the use of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Twelve subjects were recruited for a three-period cross-over study which utilized caffeine containing beverages. Each visit included 8-hour blood plasma and VAS response collection for PK and PD assessment respectively. The VAS used in the study, also called the caffeine analog scale, has been previously validated for caffeine. Population PK-PD modeling was conducted with NONMEM 7.2. Simultaneous and sequential modeling of PK-PD was attempted. Final model selection was based on parameter estimate precision, diagnostic plots, and visual predictive check (VPC) plots. Results showed that a one-compartment open model with first-order absorption and elimination best described the pharmacokinetics of caffeine. Sequential PK-PD modeling was successful and an effect compartment model with linear slope and baseline parameter best described caffeine pharmacodynamics. Diagnostic plots showed no major bias and VPC plots showed agreement between observations and predictions. The model was able to link VAS responses to caffeine concentration in healthy volunteers and may be useful in clinical trial simulations and design.

Pharmacokinetics and pharmacodynamics of Shengjiang decoction in rats with acute pancreatitis for protecting against multiple organ injury

AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction(SJD) in rats with acute pancreatitis(AP) for protecting against multiple organ injury.METHODS An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group(CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD(CG + SJD) and a model group treated with SJD(MG + SJD), both of which were orally administered with SJD(5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male SpragueDawley rats were randomly divided into a CG, an AP model group(MG), and an SJD treated AP group(SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological examination.RESULTS The MG + SJD displayed significantly shorter mean residence time(MRT) and higher clearance(CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve(AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin(IL)-6, IL-10, and tumor necrosis factor(TNF)-α levels in the MG were higher than those in the CG(P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG(P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG(P < 0.05).CONCLUSION AP may have varying effects on the pharmacokinetics of the major SJD components in rats. SJD might alleviate pathological injuries of the lung, pancreas, kidney, and intestine in rats with AP via regulating pro-and antiinflammatory responses, which might guide the clinical application of SJD for AP treatment.

Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis

AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis. METHODS Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloeemodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated. RESULTS The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-a and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG (P < 0.05), while there was no statistical difference in the MG and HDG. CONCLUSION DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

Exploring dynamic biomedical algorithm of Eurycoma longifolia Jack and its bioactive phytochemicals: A review of pharmacokinetic and pharmacodynamic implications and future prospects

Eurycoma longifolia Jack(E.longifolia) is a well-recognized traditional herbal medicine that offers a wide dynamic range of biomedical applications including anti-osteoporotic, anticancer, anti-proliferative, anti-malarial, antimicrobial, antioxidant, aphrodisiac, antiinflammatory, anxiolytic, anti-diabetic, anti-rheumatism and anti-ulcer properties.This review aims to overview the pharmacokinetic and a pharmacodynamic algorithm of E.longifolia and its bioactive components.Analysis of pharmacokinetic profile revealed that E.longifolia exhibit higher bioavailability, high volume of distribution, slow elimination rate, and does not show inhibitory effects on cytochrome P450 isoenzymes.E.longifolia has been used, alone or in combination with other pharmacological agents, in the form of crude extracts, standard extracts, or decoctions of different plant parts(i.e., herbs, shrubs, stem, leaves, and roots) for the treatment of various ailments in animals and humans.Among various bioactive constituents, eurycomanone has been found to be the most remarkable, super-stable, versatile, and most potent phytochemical(isolated or extracted from root extracts) against various types of animals and human diseases.Based on its well-established pharmacokinetic and pharmacodynamic profiles, we suggested that E.longifolia can be a well-accepted complementary and alternative medicine for the treatment of different types of human ailments.

Safety, Pharmacokinetic and Pharmacodynamic Studies of Batifiban Injection Following Single-and Multiple-Dose Administration to Healthy Chinese Subjects

Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPⅡb/Ⅲa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic （inhibition of platelet aggregation） effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 μg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h （180 μg/kg plus 2.0 μg/minokg, and 220 μg/kg plus 2.5μg/minokg） in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPⅡ b/Ⅲa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.

Optimal timing for the oral administration of DaCheng-Qi decoction based on the pharmacokinetic and pharmacodynamic targeting of the pancreas in rats with acute pancreatitis

AIM To identify the optimal oral dosing time of Da-Cheng-Qi decoction(DCQD) in rats with acute pancreatitis(AP) based on the pharmacokinetic and pharmacodynamic parameters.METHODS First, 24 male Sprague-Dawley rats were divided into a sham-operated group [NG(a)] and three model groups [4 h G(a), 12 h G(a) and 24 h G(a)]. The NG(a) and model groups were administered DCQD(10 g/kg.BW) intragastrically at 4 h, 4 h, 12 h and 24 h, respectively, after AP models induced by 3% sodium taurocholate. Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosing with DCQD. Plasma and pancreatic tissue concentrations of the major components of DCQD were determined by high-performance liquid chromatography tandem mass spectroscopy. The pharmacokinetic parameters and serum amylase were detected and compared. Second, rats were divided into a sham-operated group [NG(b)] and three treatment groups [4 h G(b), 12 h G(b) and 24 h G(b)] with three corresponding control groups [MG(b)s]. Blood and pancreatic tissues were collected 24 h after a single dosing with DCQD. Serum amylase, inflammatory cytokines and pathological scores of pancreatic tissues were detected and compared.RESULTS The concentrations of emodin, naringin, honokiol, naringenin, aloe-emodin, chrysophanol and rheochrysidin in the 12 h G(a) group were higher than those in the 4 h G(a) group in the pancreatic tissues(P < 0.05). The area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration values(AUC0→t) for rhein, chrysophanol, magnolol and naringin in the 12 h G(a) group were larger than those in the 4 h G(a) or 24 h G(a) groups. The 12 h G(a) group had a higher Cmax than the other two model groups. The IL-10 levels in the 12 h G(b) and 24 h G(b) groups were higher than in the MG(b)s(96.55 ± 7.84 vs 77.46 ± 7.42, 251.22 ± 16.15 vs 99.72 ± 4.7 respectively, P < 0.05), while in the 24 h G(b) group, the IL-10 level was higher than in the other two treatment groups(251.22 ± 16.15 vs 154.41 ± 12.09/96.55 ± 7.84, P < 0.05). The IL-6 levels displayed a decrease in the 4 h G(b) and 12 h G(b) groups compared to theMG(b)s(89.99 ± 4.61 vs 147.91 ± 4.36, 90.82 ± 5.34 vs 171.44 ± 13.43, P < 0.05). CONCLUSION Late-time dosing may have higher concentrations of the most major components of DCQD, with better pharmacokinetics and pharmacodynamics of antiinflammation than early-time dosing, which showed the late time to be the optimal dosing time of DCQD for AP.

Individualized immunosuppression: new strategies from pharmacokinetics,pharmacodynamics and pharmacogenomics

The ultimate goal of transplantation is the donor-specific immune tolerance, but at least in the first 15 to 20 years of this century, immunosuppressive agents are still the determinant of clinical outcome of transplant recipients. Individualizing patient's immunosuppression to optimize the balance between therapeutic efficacy and the occurrence of adverse events poses a great challenge to physicians. DATA SOURCES:The data in this article were taken mostly from MEDLINE (2000-2004), part of which were from the research of the authors. RESULTS:Individualized immunosuppression remains a problem because of the narrow therapeutic index and wide inter- and intra-patient variation of commonly-used im- munosuppressants. Recent progress in study of pharmaco-kinetics and pharmacodynamics improved the clinical outcome of transplant recipients. More importantly, the emergence of pharmacogenomics might provide a promising and complementary tool for traditional therapeutic drug monitoring (TDM). CONCLUSIONS:Individualizing organ recipient's immunosuppression to balance the therapeutic efficacy and the adverse events represents a great challenge to transplant clinicians. Pharmacogenomics shows great promise for an interesting and hopefully better future.

Pharmacokinetics and pharmacodynamics of lignocaine: A review

Lignocaine is an essential drug on World Health Organisation essential drug list, considered efficacious, safe and cost-effective for any health-care system. Despite its ubiquitous use in medicine and surgery, there are few detailed reviews of its pharmacokinetics and pharmacodynamics. Being an amide-type local anesthetic and Class 1b antiarrhythmic, lignocaine is most frequently used clinically for its anesthetic and antiarrhythmic benefits. However, lignocaine has important antinociceptive, immuno-modulating, and antiinflammatory properties. Information pertaining to the pharmacokinetics and pharmacodynamics of lignocaine was examined by performing a literature search of Pub Med, Embase and MEDLINE(via Ovid), pharmacology textbooks and online sources. We present a focused synopsis of lignocaine's pharmacological composition, indications for use and mechanisms of action, focusing on its anti-inflammatory, immuno-modulating and analgesia effects. In addition we review the dosing regimes and infusion kinetics of lignocaine in the clinical setting. Finally, we review the evidence for ligocaine's modulation of the inflammatory response during major surgery and its specific effects on cancer recurrence. These indirect effects of local anesthetics in tumor development may stem from the reduction of neuroendocrine responses to the stress response elicited by major surgery and tissue damage, enhanced preservation of immune-competence, in addition to opioid-sparing effects of modulating tumor growth.

Evaluation of pharmacokinetics and pharmacodynamics relationships for Salvianolic Acid B micro-porous osmotic pump pellets in angina pectoris rabbit

The work aims to investigate the in vitro release,pharmacokinetics(PK),pharmacodynamics(PD)and PK-PD relationships of Salvianolic Acid B micro-porous osmotic pump pellets(SalB-MPOPs)in angina pectoris New Zealand White(NZW)rabbits,compared with those of SalB immediate-release pellets(SalB-IRPs).The SalB plasma concentrations and Superoxide dismutase levels(PD index)were recorded continuously at predetermined time interval after administration,and the related parameters were calculated by using Win-Nonlin software.The release profile of MPOPs was more sustained than that of IRPs.PK results indicated that the mean C_(max) was significantly lower,the SalB plasma concentrations were steadier,both area under concentration-time curve from 0 to 24 h(AUC_(0-24 h))and from 0 to infinity(AUC_(0-∞))were presented larger,and both the peak concentration time(T_(max))and mean residence time(MRT)were prolonged for MPOPs,as compared with those of IRPs.PD results suggested that peak drug effect(E_(max))was lower and the equilibration rate constant(k_(e0))between the central compartment and the effect compartment was higher of MPOPs vs.those of IRPs.PKePD relationships demonstrated that the effectconcentration-time(ECT)course of MPOPs was clockwise hysteresis loop,and that of IRPs was counter-clockwise hysteresis loop.Collectively,those results demonstrated that MPOPs were potential formulations in treating angina pectoris induced by atherosclerosis.

Analysis of Pharmacokinetic/Pharmacodynamic Parameters and Dosage Regimen of Posaconazole against <i>Candida</i>spp. and <i>Aspergillus</i>spp. Using Monte Carlo Simulation

Invasive fungal infections (IFI) have recently become increasingly more prevalent, resulting in an increased risk of morbidity and mortality. Both Candida spp. and Aspergillus spp. are major causes of IFI. In this study, we aimed to evaluate the cumulative fraction of response of various dosage regimens of posaconazole against nine Candida spp. and six Aspergillus spp. in both children and adults. Monte Carlo simulation (MCS) was performed to optimize selection of posaconazole dosage regimens. For children, a dosage regimen of 120 mg/m2 posaconazole tid was sufficient to treat fungal infections caused by all six Aspergillus spp. and six of the nine Candida spp. (but was not effective against C. glabrata, C. guilliermondii and C. krusei). In contrast, a 400 mg dosage regimen of posaconazole bid achieved the target pharmacokinetic/pharmacodynamics (PK/PD) parameters against all six Aspergillus spp. and eight of the nine Candida spp. (but was not effective against C. glabrata) in the adults. Dosage regimens of 50 mg bid, 100 mg bid, or 200 mg bid were not effective. Posaconazole dosage regimens are likely to achieve their desired PK/PD targets against Candida spp. and Aspergillus spp. in both children and adults.

A genome-wide association study identifies novel genetic loci that modify pharmacokinetic-pharmacodynamic responses to clopidogrel

OBJECTIVE Genetic variants in the pharmacokinetic(PK)mechanism are the main underlying factors that modify the antiplatelet efficacy of clopidogrel.Hence,joint analysis of genetic variants that modify pharmacodynamic(PD)and PK responses to clopidogrel should be effective for identifying the genetic variants affecting the antiplatelet response to the drug.METHODS A genome-wide association study was conducted to identify new genetic loci that modify PD responses to clopidogrel and its active metabolite H4 in 115 Chinese patients with coronary heart disease(CHD).RESULTS We identified novel variants in two transporter genes(rs12456693 in SLC14A2 and rs2487032 in ABCA1)and in N6AMT1(rs2254638)associated with clopidogrel-treated P2Y12reaction unit(PRU)and plasma H4 concentration.The associations between these single nucleotide polymorphisms(SNPs)and PK parameters of clopidogrel and H4 were observed in 31 additional CHD patients(P<0.05).The new variants,together with CYP2C19*2 and clinical factors,dramatically improved the predictability of PRU variability to 37.7%compared with the published value of approximately 20%.The function of these SNPs on the activation of clopidogrel was validated in 32 liver S9 fractions,and the N6AMT1 rs2254638 T variant was found to be associated with decreased formation of H4(P=0.0386).Meanwhile,N6AMT1 rs2254638 was further identified to exert a marginal risk effect for MACE in an independent CHD patient cohort(OR:1.428,95%CI:0.978-2.086,P=0.0653,FDR=0.4726).In conclusion,we systematically identified new genetic variants as risk factors for the reduced efficacy of clopidogrel.CONCLUSION Our study findings enhanced the understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.

A genome-wide association study identifies novel genetic loci modifying pharmacokinetic - pharmacodynamic responses to clopidogrel

Aim Clopidogrel therapy is associated with a substantial variability in pharmacokinetics （PK） and pharmacodynamics （PD） responses. To date, known gene variants explain only a small proportion of the variabili- ty. A genome-wide association study （GWAS） was conducted to identify new genetic loci modifying PD responses to clopidogrel in Chinese patients with coronary heart disease （CHD）. The initial GWAS by combination analysis of PIL/PD included 115 patients with CHD. The PK validation included 31 patients with CHD and the metabolizing functional validation included 32 human liver tissues. We identified novel variants in two transporter genes （ rs12456693 in SLC14A2 and kgpl 1138762 in ABCA1 ） and in N6AMT1 （rs2254638） associated with not only clo- pidogrel on-treated P2Y12 reaction unit （PRU） （P 〈 1 × 10^-4） , but also plasma clopidogrel active metabolite H4 concentration （P 〈 1 × 10^-2）. The significant association between rs12456693, kgpl 1138762, or rs2254638 and PK parameters of clopidogrel （P 〈 1 × 10^-2） was observed in additional CHD patients. Further, the N6AMT1 rs2254638 T variant was found to be associated decreased activation of clopidogrel （P -3.86 × 10^-2）. The new variants in N6AMT1 and ABCA1, together with CYP2C19 ＊ 2, dramatically improve the predictability of PRU varia- bility to 37.7% compared with the published value of approximately 20%. The present study identifies novel genet- ic loci modifying PIL/PD responses to clopidogrel, which contributes to a better understanding of the absorption and metabolic mechanisms that influence PD responses to clopidogrel treatment.

Optimization of Dosage Regimen of Rezafungin against <i>Candida spp. </i>Based on Pharmacokinetic/Pharmacodynamic Analysis

Invasive candidiasis was the most common nosocomial fungal infection with high morbidity and mortality, which is mainly occurring in immunodeficiency and critical patients. Echinocandins were recommended as first-line drugs for the treatment and prevention of invasive candidiasis. In our study, we aimed to optimize the dosage of Rezafungin against Candida spp. based on pharmacokinetic/pharmacodynamics (PK/PD) analysis. We collected the published data about pharmacokinetic parameters of rezafungin and the MIC distribution of Candida spp. on rezafungin. Monte Carlo simulation was used to calculate probability of target attainment and a cumulative fraction of response to assess the best dosing regimen. The optimal dosage regimen for C. albicans and C. glabrata was 50 mg IV, and the optimal dosage regimen for C. parapsilosis was 100 mg IV. Lastly, rezafungin has an excellent antifungal effect on C. albicans, C. glabrata and C. parapsilosis.

Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction

Patients with cancer have a high inherent risk of infectious complications.In addition,the incidence of acute and chronic kidney dysfunction rises in this population.Antiinfective drugs often require dosing modifications based on an estimate of kidney function,usually the glomerular filtration rate(GFR).However,there is still no preferential GFR formula to be used,and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR.In most cases,the anti-infective therapy should start with an immediate and high loading dose.Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment.Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations(e.g.,beta lactam antibiotics,penems,vancomycin,antiviral drugs).Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations(e.g.,aminoglycosides,daptomycin,colistin,quinolones).Our group created a pharmacokinetic database,called NEPharm,hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy.To avoid the risk of either too low or too infrequent peak concentrations,we prefer the eliminated fraction rule for dose adjustment calculations.

Characteristics of the anti-dementia drug system of Zisu Fang preparations based on pharmacokinetic and pharmacodynamic analysis

Objectives:To investigate the pharmacokinetics (PK) and pharmacodynamics (PD)of index components of Zisu Fang preparations and additionally analysis the anti-dementia drug system characteristics.Methods:A PK-PD-drug interaction (DI) method was applied to determine the characteristics of index components of Zisu Fong preparations in vivo.Results:In the PK study,maximum plasma concentration,area under the plasma concentration-time curve,and mean residence time of index components of Zisu Fang preparations were higher in the memory-deficit model group than in the control group.This suggested that the index components of Zisu Fang preparations had an affinity for the state of dementia in this model.In the PD study,at the peak time points of anti-dementia efficacy (0.17 h and 1 h),the plasma concentrations of index components of Zisu Fang preparations reached the first or second largest plasma concentration peak or were close to the plasma concentration peak,and showed positive correlation between these two peaks,indicating that the index components of Zisu Fang synergistically exerted an anti-dementia effect.According to the association analysis of PK-PD-DI,baicalin,rosmarinic acid,salvianolic acid B,matrine,and tanshinone ⅡA were the main active ingredients of the anti-dementia drug system of Zisu Fang preparations in vivo,but were only efficacious against dementia when all five components were present at a specific concentration and proportion.Conclusions:Based on the PK and PD correlation analysis,baicalin,rosmarinic acid,salvianolic acid B,matrine,and tanshinone ⅡA are the main active ingredients of Zisu Fang preparations with regard to its anti-dementia effects,and represent the basic characteristics of drug system:natures,synergy,and affinity.

Pharmacokinetics of Native r-SAK in Rabbit's Femoral Artery Thrombosis Model

Objective: To study the pharmacokinetics of native r SAK in rabbit's femoral artery thrombosis model, the “lytic circle' method was used to determine plasma levels of r SAK. Methods: Thirty New Zealand rabbits were randomly assigned to the control (saline 10 ml, 30 min), r SAK low dose (0.25 mg/kg, 30 min), medial dose (0.50 mg/kg, 30 min), high dose (1.00 mg/kg, 30 min), single bolus (0.50 mg/kg, 2 min) and conjunctive therapy (initiated with heparin 200 U/kg, followed by infusion of r SAK 0.50 mg/kg for 30 min, and subsequently infused heparin 50 U/(kg·h) to endpoint) groups. The right femoral artery thrombosis model in rabbit was made by balloon injury, then the thrombolytic agents were infused through parallel ear vein and the blood samples were collected pre thrombolysis and at different time post thrombolysis to determine the plasma levels of r SAK by “lytic circle' method, the plasma levels of r SAK were processed by pharmacokinetic computing procedure to fit the model. Results: The plasma levels of r SAK and the diameters of lytic circles showed a pretty good linear correlation under the scope of 2.0×10 4 2.0×10 6 U/L, and the averaged recycle rate was (96.05±11.35)%(RSD =±11.82%).All peak concentration time in each infusion group was 30 min, and the peak concentrations positively correlated with the doses administrated in infusion groups(r=0.999 98, P <0.000 1). In single bolus group, Peak concentration time was 2 min, and the peak concentration reached (5.16±1.02) mg/L, which was significant higher than that in the same dose r SAK infusion group ( P <0.01). In conjunctive therapy group, the peak concentration showed no significant difference from that in the same dose r SAK infusion group ( P >0.05). The plasma levels of r SAK fit in two compartment model as processed by pharmacokinetic computing procedure in each group. Conclusion: The “lytic circle' method is a simple, practical and reliable method to determine the plasma level of r SAK, and the pharmacokinetics of native r SAK infusion fits in two compartment model in rabbit's femoral artery thrombosis model.