Alterations In Pharmacokinetic Parameters Research Articles

'Under pressure': The role of therapeutic drug monitoring in the treatment of hypertension.

Antihypertensive drugs do not qualify as optimal candidates for therapeutic drug monitoring (TDM), given their obvious physiological effect, the absence of a clear relationship between drug concentrations and pharmacodynamic outcomes and their wide therapeutic range. However, since non-adherence is a major challenge in hypertension management, using drug concentrations can be of value to identify non-adherence as a first step towards better blood pressure control. In this article we discuss the key challenges associated with measuring and interpreting antihypertensive drug concentrations that are important when TDM is used to improve non-adherence. Additionally, we elaborate on the role of TDM in optimizing antihypertensive drug treatment besides addressing non-adherence by highlighting its value in specific patient groups with altered pharmacokinetic parameters such as female vs. male or elderly patients.

Effect of Ciklavit® - (A Poly-Herbal Formulation) on the Pharmacokinetics of Proguanil in Healthy Nigerian Volunteers

The therapeutic efficacy of herbal medicines in the treatment of human diseases or disorders has gained more attention over the years. A survey established that approximately 15 % of patients receiving orthodox medicine also take herbal products, and among these, potential adverse herbto-drug interactions were observed in 40 % of patients. Recently, there have been reports of herbdrug interactions which have impacted on wellness of users resulting in toxicity or loss of therapeutic efficacy of either the herb or the orthodox drug when co-administered. These reports make herb-drug interactions a research area of public interest. This study was embarked upon to evaluate the effect of Ciklavit® used for the management of sickle cell anaemia on the pharmacokinetic profile of proguanil tablets in healthy Nigerian volunteers. Twelve healthy participants were recruited and completed the study after signing a consent form. The study was performed using a single dose, two-way randomized crossover design. The participants were randomly grouped into control and treatment. The treatment group were administered proguanil tablets with Ciklavit® while the control group took proguanil with water only. The blood and urine samples collected at different time interval for 24 hours were analyzed using HighPerformance Liquid Chromatography. The results obtained, demonstrated that co-administration of Ciklavit® with proguanil altered pharmacokinetic parameters of proguanil but the difference in values were found to be statistically insignificant (p>0.05). The study demonstrated that there are no significant pharmacokinetic interactions between proguanil and Ciklavit® hence the two medicinal agents can be co-administered.&nbsp

ALTERATION OF PHARMACOKINETIC PARAMETERS OF PROTON PUMP INHIBITORS USING TRANSDERMAL DRUG DELIVERY SYSTEM

Objective: The present study was aimed to find out the effect of transdermal patches of proton pump inhibitors pantoprazole and esomeprazole on the alteration of pharmacokinetic parameters of these drugs. Methods: The transdermal patches were formulated by the solvent evaporation technique using polymers HPMC E5 with PVP K 30 and HPMC E5 with Eudragit L100 in different ratios. The best formulation from each of the drug pantoprazole and esomeprazole was selected and administered to rabbits and the plasma drug concentration was compared with the marketed formulation. The pharmacokinetic parameters such as maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under the curve (AUC), area under first moment curve (AUMC), elimination rate constant (λz), biological half-life (t1/2), and mean residence time (MRT) were determined. Results: The plasma drug concentration vs time curve shows the extended-release of the drugs pantoprazole and esomeprazole when compared with the marketed formulation. The results show that there is no change in the peak plasma concentration, but a significant difference was observed in all the pharmacokinetic parameters. The AUC showed 6 fold increase for pantoprazole from 8.91 to 55.20 μg*h/ml and 3.5 fold increase for the drug esomeprazole from 7.86 to 28.53 μg*h/ml, and the mean residence time also showed 2 fold increase for the transdermal patches when compared with the marketed formulations. Conclusion: The increase in tmax, AUC, and MRT values of the formulated transdermal patches with the values of the marketed formulation of both the drugs, revealed that the transdermal patches can be used to deliver the drug for an extended period and also can alter the pharmacokinetics of pantoprazole and esomeprazole.

Pharmacodynamic and pharmacokinetic interactions of hydroalcoholic leaf extract of Centella asiatica with valproate and phenytoin in experimental models of epilepsy in rats

Ethnopharmacological relevanceCentella asiatica (CA) is commonly used herbal medicine for treatment of epilepsy. CA has CYP2C9, CYP2D6 and CYP3A4 enzymes inhibition property and used as an adjuvant therapy with conventional antiepileptic drugs (AEDs). That may be responsible for herb-drug interaction. Aim of the studyThe present study was planned to evaluate interactions profile of hydroalcoholic extract Centella asiatica (HECA) with antiepileptic drugs in experimental models of epilepsy in rats. Materials and methodsWistar rats (175–200 g) were used. In the pharmacodynamic interaction study, seizures were induced using pentylenetetrazole (PTZ) (60 mg/kg, i.p.) and maximal electroshock seizure (MES) (70 mA for 0.2 s). The therapeutic and sub-therapeutic doses of valproate (VPA) and phenytoin (PHT) were co-administrated with HECA in PTZ and MES model of seizures respectively. Behavioural parameters were assessed using elevated plus maze test and passive avoidance paradigm. Rat brain oxidative stress parameters were also assessed. In the pharmacokinetic interaction study, the serum levels of the VPA and PHT were estimated at different time intervals by HPLC and pharmacokinetic parameters were analyzed by WinNonlin software. ResultsThe VPA and PHT produced complete protection against seizures in their therapeutic doses but not with sub-therapeutic doses. However, co-administration of HECA with a sub-therapeutic dose of VPA and PHT enhanced the protection of seizures and significantly (p < 0.001) attenuated the seizure induced oxidative stress and cognitive impairment. It also significantly increased (p < 0.001) serum levels of VPA and PHT. The alterations in pharmacokinetic parameters (maximum serum concentration, area under the curve, clearance) of AEDs were also found with co-administration of HECA. ConclusionThe results suggested that co-administration of HECA could improve the therapeutic efficacy of VPA and PHT. But, alteration in pharmacokinetic parameters revel that needs critical medical supervision to avoid any toxic reactions.

Pharmacokinetics of meropenem in burn patients with infections caused by Gram-negative bacteria: Are we getting close to the right treatment?

Infections caused by multidrug-resistant Gram-negative bacteria are associated with high mortality. A relevant concern is the efficacy of antibiotic therapy in burn patients in whom pathophysiological changes strongly influence pharmacokinetic (PK) parameters. This study aimed to describe the PK parameters of meropenem in a population of burn patients. Blood samples were collected immediately before and 2 h and 5 h after the start of intravenous drug administration. Plasma meropenem concentrations were determined using an ultra-performance liquid chromatography-photodiode array method. Seventeen burn patients were enrolled in the study. Thirteen patients (76%) were treated with meropenem for infections byPseudomonas aeruginosa or Acinetobacter baumannii isolated from blood or wounds. Mean Cmax, Cmin, AUC0-24, half-life, drug clearance and volume of distribution were 28.9 mg/L, 3.7 mg/L, 280.2 mg h/L, 2.0 h, 19.0 L/h and 44.4 L, respectively. Six patients (35%) achieved a Cmin ≥3.3 mg/L and seven patients (41%) achieved a Cmax ≥ 28.4 mg/L, whilst nine patients (53%) achieved an AUC0-24 of >226 mg h/L. Given a minimum inhibitory concentration (MIC) of 0.5 mg/L, all patients satisfied the target AUC/MIC of >125, but when the MIC rises to 2 mg/L (the ECOFF), only five patients reached the desired AUC/MIC. Regarding fT>MIC at an MIC of 2 mg/L with a 2-h infusion time, 13 patients (76%) achieved the PK target (>75%). These data suggest that a combined 2-h infusion with a higher dosage of meropenem, including a loading dose, may be successful to achieve effective PK parameters.

Evaluation of treatment options for methicillin-resistant Staphylococcus aureus infections in the obese patient.

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major cause of infection in both the hospital and community setting. Obesity is a risk factor for infection, and the prevalence of this disease has reached epidemic proportions worldwide. Treatment of infections in this special population is a challenge given the lack of data on the optimal antibiotic choice and dosing strategies, particularly for treatment of MRSA infections. Obesity is associated with various physiological changes that may lead to altered pharmacokinetic parameters. These changes include altered drug biodistribution, elimination, and absorption. This review provides clinicians with a summary of the literature pertaining to the pharmacokinetic and pharmacodynamic considerations when selecting antibiotic therapy for the treatment of MRSA infections in obese patients.

A Randomized Pharmacokinetic and Pharmacodynamic Evaluation of Every 8-Hour and 12-Hour Dosing Strategies of Vancomycin and Cefepime in Neurocritically ill Patients.

Neurocritically ill patients have clinically significant alterations in pharmacokinetic parameters of renally eliminated medications that may result in subtherapeutic plasma and cerebrospinal fluid antibiotic concentrations. We conducted a prospective randomized open-label study of adult neurocritically ill patients treated with vancomycin and cefepime. Vancomycin 15mg/kg and cefepime 2g were dosed at every-8- or 12-hour intervals. The primary outcomes were the achievement of pharmacodynamic (PD) targets related to time of unbound drug above minimum inhibitory concentrations (MIC) for 60% or more of the dosing interval (fT>MIC ≥60%) for β-lactams and ratio of 24-hour area under the curve (AUC):MIC of 400 or greater for vancomycin. Twenty patients were included in the study. They were divided equally between the every-12-hour and every-8-hour dosing groups. Patients (mean age 51.8±11yrs) were primarily male (60%) and white (95%), and most had an admission diagnosis of intracranial hemorrhage (80%). Compared with the every-12-hour group, the every-8-hour vancomycin group achieved target trough concentrations (higher than 15μg/ml) significantly more frequently at initial measurement (0% vs 80%, p<0.01) and at 7-10days (0% vs 90%, p=0.045) and achieved PD targets more frequently at increasing MICs. Similarly, compared with every-12-hour dosing, the every-8-hour cefepime dosing strategy significantly increased PD target attainment (fT>MIC ≥60%) at an MIC of 8μg/ml (20% vs 70%, p=0.02). This study demonstrated that more frequent dosing of vancomycin and cefepime is required to achieve optimal PD targets in adult neurocritically ill patients. The need for increased total daily doses is potentially secondary to the development of augmented renal clearance.

Effect of Tinospora cordifolia aqua-alcoholic extract on pharmacokinetic of Glibenclamide in rat: An herb-drug interaction study

Tinospora cordifolia (TC) has been used as a complimentary/alternative medicine against diabetes. Considering its potential to modulate metabolic enzymes, Tinospora cordifolia extract (TCE) may influence the metabolism of the antidiabeic drug Glibenclamide following co-administration. Accordingly, this work was undertaken to evaluate impact of TCE on fate of Glibenclamide. Activity of clinically important Cytochrome P450 isoenzymes were inhibited in the order of CYP2C9 > CYP2D6 > CYP2C19 > CYP1A2 > CYP3A4. Formations of metabolites were inhibited with increasing concentration of TCE in both rat and human liver microsomes. TCE was co- administered in three different groups (0, 100 and 400 mg/kg) with Glibenclamide at 1 mg/kg dose to observe the alteration in pharmacokinetic parameters of Glibenclamide. The rats were pretreated with 0 (vehicle), 100 and 400 mg/kg dose of TCE b.i.d for 14 days and on the 14th day all three groups were administered with 1 mg/kg Glibenclamide. Pharmacokinetic parameters were analyzed based on plasma concentrations of Glibenclamide from all the groups by LC–HRMS methods using Glipizide as an internal standard. At 400 mg/kg dose, a marked increase in the bio availability of Glibenclamide was observed with a significant delay of Tmax and suppression of clearance.

The effectiveness and safety of pharmacotherapy against the background of application of Gliquidone

The study was carried out to investigate using rabbits in vivo effect of Gliquidone on functional activity of protein-carrier of glycoprotein-P (P-gp, ABCB1-protein). The activity of P-gp was evaluated according pharmacokinetics of its marker substrate - Fexofenadine after single endogastric introduction. The application of Gliquidone in dosage of 10 mg per 1 kg of body mass during 14 days resulted in no alteration of concentration of Fexofenadine, period of its partial ejection, area under pharmacokinetic curve “concentration-time” from zero to last point of blood sampling, area under pharmacokinetic curve “concentration-time” from zero to infinity and also time of holding of marker substrate, total clearance and absorption coefficient. All this testifies absence of effect of Gliquidone on functional activity of protein-carrier at the level of integral organism. No alterations of pharmacokinetic parameters of Fexofenadine at the 5th day of cessation of Gliquidone were observed.

Size Dependent Variations of Phospholipid Based Vesicular Drug Carriers in Systemic Drug Activity

Lipid based vesicular drug delivery system, one of the emerging technologies designed for addressing the delivery challenges of conventional drug delivery methods, has widespread applications in chemotherapeutics, immunotherapeutics, recombinant DNA technology, membrane biology and also as a diagnostic tool in different biological field. The enclosed phospholipid bilayer spherical structure, typically known as liposome, is a versatile vesicular delivery system to carry hydrophilic/hydrophobic drug generally efficiently to the site of action leading to reduced non-specific toxicity and improved bioavailability of the therapeutic moiety. Efficacy of drug encapsulated in liposome depends mainly on the circulation amount of liposome and its residence time, in vivo drug release, drug accumulation in the target site and uptake of the formulation in the reticuloendothelial system. Liposomal formulation factors that dictate those actions are liposomal size (hydrodynamic diameter), surface charge, lipid composition and steric stabilization. Variation in liposomal size shows around 100 fold alterations in pharmacokinetic parameters and systemic activity while the other factors such as surface charge, lipid composition and steric stabilization bring only about 10 fold changes in those properties. The findings indicate the critical role of vesicular size in liposomal efficacy. In the present review the effect of size-variation of liposome on systemic activity of drug as well as its pharmacokinetic profile will be discussed to understand the rational designing of liposomal preparation to maximize therapeutic activity of a drug at desired magnitude and to provide a wide range of product applications such as immunological vaccines, chemotherapy, antimicrobial therapy etc.

Pharmacokinetics and pharmacodynamics of antibiotic therapy

Antibiotic agents are crucial pillars in intensive care medicine and must be used rationally and sensibly. In the case of critically ill patients optimal dosing with respect to pharmacokinetic and pharmacodynamic principles (PK/PD) can be vital. Preclinical results demonstrated important differences between antibiotic classes and gave rise to differing clinical dosing strategies, e.g. high dose once daily regimens for aminoglycosides or extended/continuous infusion of betalactams. Critically ill patients with altered pharmacokinetic parameters and infections by pathogens with low susceptibility are most likely to benefit from PK/PD-guided therapy.

Application of a physiologically based pharmacokinetic model informed by a top-down approach for the prediction of pharmacokinetics in chronic kidney disease patients.

Quantitative prediction of the impact of chronic kidney disease (CKD) on drug disposition has become important for the optimal design of clinical studies in patients. In this study, clinical data of 151 compounds under CKD conditions were extensively surveyed, and alterations in pharmacokinetic parameters were evaluated. In CKD patients, the unbound hepatic intrinsic clearance decreased to a similar extent for drugs eliminated via hepatic metabolism by cytochrome P450, UDP-glucuronosyltransferase, and other mechanisms. Renal clearance showed a similar decrease to glomerular filtration rate, irrespective of the contribution of tubular secretion. The scaling factor (SF) obtained from the interquartile range of the relative change in each parameter was applied to the well-stirred model to predict clearance in patients. Hepatic and renal clearance could be successfully predicted for approximately half and two-thirds, respectively, of the applied compounds, showing the high utility of SFs. SFs were also introduced to a physiologically based pharmacokinetic (PBPK) model, and the plasma concentration profiles of 12 model compounds with different elimination pathways were predicted for CKD patients. The PBPK model combined with SFs provided good predictability for plasma concentration. The developed PBPK model with information on SFs would accelerate translational research in drug development by predicting pharmacokinetics in CKD patients.

Obesity and hormonal contraceptive efficacy.

Obesity is a major public health concern affecting an increasing proportion of reproductive-aged women. Avoiding unintended pregnancy is of major importance, given the increased risks associated with pregnancy, but obesity may affect the efficacy of hormonal contraceptives by altering how these drugs are absorbed, distributed, metabolized or eliminated. Limited data suggest that long-acting, reversible contraceptives maintain excellent efficacy in obese women. Some studies demonstrating altered pharmacokinetic parameters and increased failure rates with combined oral contraceptives, the contraceptive patch and emergency contraceptive pills suggest decreased efficacy of these methods. It is unclear whether bariatric surgery affects hormonal contraceptive efficacy. Obese women should be offered the full range of contraceptive options, with counseling that balances the risks and benefits of each method, including the risk of unintended pregnancy.

PP197—Therapeutic Drug Monitoring of Vancomycin and Aminoglycosides in an Intensive Care Unit, a Retrospective Study

Critically ill patients may display altered pharmacokinetic parameters. Therapeutic drug monitoring (TDM) is essential to optimize the use of antibiotics in intensive care units. Many TDM assessments may be inappropriate as a result of improper interpretation or collection timing. We assessed the practice of TDM of vancomycin and aminoglycosides in an adult intensive care unit.

Toxicity of cytotoxic agents to granulocyte–macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats

Increased risk of anticancer chemotherapy in seriously obese patients is known. Obesity may be among factors that predict treatment-related toxicity during chemotherapy. We investigated whether functional changes in granulopoiesis may also contribute to increased myelotoxicity in addition to the known alterations of pharmacokinetic parameters in obesity. Hemopoiesis – as measured by cellularity, frequency of granulocyte–macrophage progenitors (CFU-GM) and total CFU-GM content of the femoral bone marrow – did not differ in obese, insulin resistant Zucker rats compared with Wistar rats. Nevertheless increased sensitivity of their CFU-GM progenitor cells to cytotoxic drugs was found by culturing them in vitro in the presence of carboplatin, doxorubicin and 5-fluorouracil. All drugs were more toxic on CFU-GM progenitor cells of insulin resistant Zucker rats than on CFU-GM cells of the control strain. This might be based on metabolic disorders, at least in part, because we could demonstrate a similar increase in toxicity of the studied anticancer drugs to the CFU-GM progenitors originated from the non-obese but insulin resistant Goto-Kakizaki rats in the same dose ranges. After in vivo administration of rosiglitazone, an insulin sensitizer, the anticancer drug sensitivity of CFU-GM progenitors of Goto-Kakizaki rats was decreased concurrently with improvement of insulin resistance. Although the increased treatment-related myelotoxicity and mortality are well-known among obese patients with malignant diseases, only the altered half lives, volumes of distribution and clearances of cytotoxic drugs are thought to be the underlying reasons. According to our knowledge the results presented here, are the first observations about an impaired granulopoiesis in obese animals.

Pharmacokinetic Effects of Bariatric Surgery

To evaluate the effect of bariatric surgery on the pharmacokinetics of medications. EMBASE (1980-September 2011), PubMed (1947-September 2011), MEDLINE (1948-September 2011), and International Pharmaceutical Abstracts (1970-September 2011) were searched for the following terms: gastric bypass or stomach bypass or bariatric surgery, and pharmacokinetic. All English-language primary literature that reported pharmacokinetic parameters for orally dosed medications in post-bariatric surgery patients was evaluated, with the exception of studies involving the jejunoileal bypass method. Worldwide, the incidence of obesity is increasing and so are options for managing it, including bariatric surgery. Major alterations to the physical structure of the gastrointestinal tract may cause changes in pharmacokinetic parameters of oral medications, which theoretically could lead to increased or decreased drug exposure. We reviewed 11 prospective trials, 5 of which were available only as abstracts and all of which were small with relatively low power (n = 6-36). The studies were split almost equally between using subjects as their own controls or using separate control subjects; 1 study used historical data as the control. Results were varied, highlighting the multifactorial nature of pharmacokinetics. Drugs such as atorvastatin, which undergo presystemic intestinal metabolism via CYP3A, may show increased bioavailability, whereas those such as amoxicillin, which rely on transport mediators, may be decreased. Most of the studies lacked sufficient power to show significant changes in post-bariatric surgery patients. Bariatric surgical procedures may result in altered pharmacokinetic parameters, but the literature is lacking in sufficient quantity and quality of studies to make solid conclusions and recommendations. Until more studies of sufficient power are completed, clinicians should closely monitor these patients in the immediate and distant postsurgical period for signs of both drug efficacy and toxicity and adjust their medications as required.

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

In the evolving paradigm of drug development it is a reasonable strategy to avoid and/or anticipate potential risks in drug development for select drugs by performing in vitro and/or preclinical studies in appropriate animal models. The availability of acute renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic disposition of drugs and associated metabolites in conditions that mimic the pathophysiology of the disease in humans. Such studies may help in drug(s) selection for development, differentiating certain drug classes, and/or arriving at a dose strategy decision in the clinic. Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol (CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The published pharmacokinetic disposition data has unequivocally suggested that ARF conditions leads to decreased renal elimination of the drug and associated metabolites; however, the influence on the overall body clearance is dependent on the propensity of the contribution of renal versus non-renal mechanisms of elimination. In the case studies assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35% of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered exposure, in ARF rat models relative to control rats. Interestingly, ARF can have an overall impact on drug absorption, distribution, metabolism, local transport and biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted with caution during ARF since there is the potential for competiting pathways to co-exist. For instance, due to reduced renal elimination as a result of kidney insult caused by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism. However, there may be instances where uraemic toxins floating in the circulation may block the metabolism and/ or may also retard the absorption process. This review covers: 1) an illustration of a number of case studies providing tabulated information on the key altered pharmacokinetic parameters observed in ARF and the hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption, distribution, metabolism, excretion and efflux transport related changes observed during ARF; 3) a general framework for drug development strategies and 4) a succinct discussion on the overall perspectives of the applicability of ARF rat models.

Pharmacokinetics of Deferiprone in Patients with β-Thalassaemia : Impact of Splenectomy and Iron Status.

Iron-rich transfusions and/or a compensatory increase in iron absorption ultimately result in iron loading in patients with β-thalassaemia. Hence, without iron chelation, iron accumulates relentlessly. Deferiprone has been shown to be capable of reducing the iron burden in patients with b-thalassaemia. However, there is wide interpatient variation in deferiprone-induced urinary iron excretion (UIE). We hypothesized that splenectomy and iron status might influence the pharmacokinetic profiles of deferiprone in patients with β-thalassaemia/haemoglobin E, and the present study was aimed at examining this hypothesis. Thirty-one patients with β-thalassaemia/haemoglobin E (20 splenecto-mized and 11 non-splenectomized patients) were enrolled in the study. After an overnight fast, the subjects received a single oral dose of deferiprone 25 mg/kg of body weight. Blood samples were collected pre-dosing and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after dosing. Urine output was pooled and collected at 0-2, 2-4, 4-8, 8-12 and 12-24 hour intervals. Serum and urine concentrations of deferiprone and its metabolite deferiprone glucuronide were determined using a validated high-performance liquid chromatography method. Serum deferiprone-chelated iron and UIE were determined using a validated colourimetric method. No significant difference in the pharmacokinetic parameters of non-conjugated deferiprone was observed between splenectomized and non-splenectomized patients. However, the maximum serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) from time zero to infinity (AUC∞) values of deferiprone glucuronide were significantly lower (both p < 0.05) in splenectomized patients (median 53.2µmol/L and 12 634 µmol · min/L, respectively) than in non-splenectomized patients (median 70.5 µmol/L and 20 601 mmol · min/L, respectively). The Cmax and the AUC from time zero to the time of the last measurable concentration (AUClast) values of serum deferiprone-chelated iron, as well as UIE, were significantly higher (p < 0.001) in splenectomized patients (median values 7.1 µmol/L, 1645 mmol · min/L and 77.1 mmol, respectively) than in non-splenectomized patients (median values 3.1 µmol/L, 545 mmol · min/L and 12.5 µmol, respectively). Urinary excretion of non-conjugated deferiprone and deferiprone glucuronide did not differ between the two groups. Further analyses using multiple linear regressions indicated that the iron profiles (non-transferrin-bound iron and ferritin) were significant predictors of the pharmacokinetic parameters of non-conjugated deferiprone, deferiprone-chelated iron and UIE. In addition, splenectomy status was identified as the strongest predictor of the AUClast of deferiprone-chelated iron and UIE. Both iron and splenectomy status have significant effects on the pharmacokinetics and iron chelation efficacy of deferiprone. A greater degree of iron overload in splenectomized patients results in alterations in pharmacokinetic parameters (the Cmax and AUC) of deferiprone glucuronide and deferiprone-chelated iron, as well as a significant increase in UIE.

Effect of Cimetidine on the Transport of Quinolone Antibiotics in Caco-2 Cell monolayers

Cimetidine, a substrate for P-glycoprotein (P-gp), is a well known drug interacting with a variety of drugs and results in alteration of pharmacokinetic parameters by concomitant administration. The aim of present study was to investigate whether cimetidine affects the transport of various quinolone antibiotics in human colorectal cancer cell line (Caco-2) system which has been typically used to investigate drug transport via P-gp. The apparent permeability coefficients (P<TEX>$_{app}$</TEX>) value of 9 quinolone antibiotics in the co-treatment with cimetidine was examined. Apical to basolateral (AP-to-BL) transport of fleroxacin in the co-treatment with cimetidine was increased to 1.5-fold (p<0.01) compared with that of fleroxacin alone, whereas basolateral to apical (BL-to-AP) transport of fleroxacin was decreased to 0.83-fold significantly (p<0.05). Ofloxacin was decreased to 0.8-fold (p<0.01) and 0.72-fold (p<0.01) significantly in AP-to-BL and BL-to-AP direction, respectively by cimetidine cotreatment. The P<TEX>$_{app}$</TEX> values of gatifloxacin, moxifloxacin, ciprofloxacin and rufloxacin also were changed by cimetidine. These results have a potential that cimetidine influences on the pharmacokinetics of quinolone antibiotics. It suggests that careful drug monitoring and dosage adjustment may be necessary during the co-administration of quinolone antibiotics with cimetidine.

Effect of Ketoconazole on the Pharmacokinetics of Ornidazole - A Possible Role of P-Glycoprotein and CYP3A

The influence of ketoconazole, a modulator of P-glycoprotein (P-gp), on the exsorption of ornidazole from everted sacs of rat intestine (duodenum, jejunum and ileum) was investigated. The effect of ketoconazole pretreatment on the pharmacokinetics of ornidazole was also studied in eight healthy human volunteers. After overnight fasting ornidazole 500 mg was administered before and after pretreatment with ketoconazole 200 mg once daily for 7 days. Serum samples were analyzed by reversed phase HPLC. Significant differences were observed in pharmacokinetic parameters C(max), AUC(0-t), AUC(0-infinity), T(max) and clearance. Ornidazole is believed to be metabolized through CYP3A and it has considerable intestinal efflux, which was observed from the in vitro study. The altered pharmacokinetic parameters can be attributed to ornidazole efflux from the blood to the intestine and its metabolism by CYP3A in the intestine.