bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of Effect of Erythromycin and Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Steady‐State Intranasal Levocabastine
Authors: Pesco‐Koplowitz Luana , Hassell Alan , Lee Peter , Zhou Honghui , Hall Nancy , Wiesinger Barbara , Mechlinski Witold , Grover Matthew , Hunt Thomas , Smith Randall , Travers Suzanne
Published: July 2003

The single‐dose effects of the cytochrome P‐450 inhibitors erythromycin and ketoconazole on the steady‐state pharmacokinetics and electrocardiographic repolarization pharmacodynamics of intranasal levocabastine, a potent and selective H1‐receptor antagonist, were evaluated in healthy young male subjects. Two randomized, open‐label, placebo‐controlled, two‐way crossover studies were performed. Levocabastine nasal spray was administered as two sprays per nostril (0.05 mg/spray) twice daily (for a total daily dose of 0.4 mg) for 6 days. On Day 7, a single dose of 0.2 mg was administered followed immediately by a single dose of either oral placebo, erythromycin 333 mg, or ketoconazole 200 mg. In all treatment groups, levocabastine was rapidly absorbed, with peak plasma concentrations reached at approximately 3 hours in the erythromycin study and 2.8 hours in the ketoconazole study. The mean terminal half‐life was approximately 45 and 44 hours, respectively. In both studies, mean steady‐state plasma concentrations and pharmacokinetics of levocabastine following the single doses of erythromycin or ketoconazole were not significantly different from corresponding values seen with the concomitant administration of the placebo. No clinically significant mean changes from baseline in QT or QTc (QT corrected for heart rate) intervals occurred in any of the treatment groups, and none of the subjects in either study experienced abnormally prolonged QTc intervals. Intranasal levocabastine was well tolerated, with no difference in the incidence of adverse events between treatment groups in either study; adverse events were generally mild in severity. Since levocabastine undergoes only minimal hepatic metabolism and is not a substrate for or an inhibitor of cytochrome P‐450, the likelihood of systemic drug interactions with drugs affecting the cytochrome P‐450 system is minimal.
The Effect of Food on the Oral Bioavailability and the Pharmacodynamic Actions of the Insulinotropic Agent Nateglinide in Healthy Subjects
Authors: Karara Adel H. , Dunning Beth E. , McLeod James F.
Published: July 2003

Nateglinide (Starlix®, SDZ DJN 608 or A‐4166), a new insulinotropic agent, is intended to be administered prior to a meal in order to improve early insulin release in non‐insulin‐dependent diabetes mellitus patients. The effects of a meal on the oral bioavailability and pharmacodynamic actions of nateglinide were investigated. Twelve healthy male subjects completed this randomized, single‐dose, four‐way crossover study in which each subject received a 60 mg dose of nateglinide 10 minutes before the start of and immediately after a high‐fat breakfast meal. In addition, each subject received a single 30 and 60 mg dose of nateglinide under fasting conditions. Plasma and urine concentrations of nateglinide were determined by an HPLC method while plasma glucose and insulin concentrations were measured by standard immunoassay methods. Compared to the fasted state, administration of nateglinide 10 minutes before the meal was associated with an increase in the rate of absorption (12% increase in Cmax and 52% decrease in tmax), while there was no significant effect on the extent of absorption (AUC). Alternatively, when nateglinide was given after the meal, a food effect was observed that was characterized by a decrease in the rate of absorption: 34% decrease in Cmax and a 22% increase in tmax but no significant effect on AUC. Nateglinide was rapidly eliminated with plasma t1/2 = 1.4 hours. Its plasma renal clearance, 20.7 ml/min, appears to be due mostly to active tubular secretion. However, only 13% to 14% of the dose is recovered as nateglinide in the urine. The 30 and 60 mg tablets were dose proportional in terms of both AUC and Cmax; both tmax and t1/2 were dose independent. Regardless of timing, the combination of a meal and nateglinide produced a larger increase in insulin levels than did nateglinide alone. Meal‐related glucose excursions were eliminated when nateglinide was taken prior to the meal. Thus, the rapid onset/short duration stimulation of insulin release by nateglinide should allow good control of prandial hyperglycemia while limiting exposure to hyperinsulinemia.
Coadministration of Short‐Term Zolpidem with Sertraline in Healthy Women
Authors: Allard Stéphane , Sainati Stephen M. , Roth‐Schechter Barbara F.
Published: July 2003

This study was undertaken to determine whether there are pharmacokinetic (PK) interactions between zolpidem, a hypnotic, and sertraline, an antidepressant. Twenty‐eight healthy female volunteers received a single dose of zolpidem alone and five consecutive dose(s) of zolpidem 10 mg in the presence of chronic doses (19 days) of sertraline 50 mg. Using HPLC, plasma levels of zolpidem, sertraline, and N‐desmethylsertraline were determined at different times throughout the study and PK parameters derived. Compared to zolpidem alone, the T1/2 of the first dose of zolpidem in the presence of sertraline was reduced, the C max of the fifth zolpidem dose in the presence of sertraline was significantly increased, and its Tmax was significantly reduced. After five doses of zolpidem, the AUC of sertraline (–6%) and the Cmax of N‐desmethylsertraline (+13%) were changed. There were no next‐day effects of zolpidem on the Digit Symbol Substitution Test, and both drugs were well tolerated. Overall, coadministration of sertraline 50 mg and zolpidem 10 mg appears to be safe in healthy females but could result in a shortened onset of action and increased effect of zolpidem.
Effects of Glucocorticoids and Cyclosporine on IL‐2 and IκBα mRNA Expression in Human Peripheral Blood Mononuclear Cells
Authors: Briggs William A. , Han Su‐Hua , Miyakawa Horoshi , Burdick James F. , Kwon H. Moo
Published: July 2003

To evaluate molecular mechanisms that might account for the heterogeneity in the in vitro responsiveness of individual subjects' peripheral blood mononuclear cells (PBMC) to immunosuppressive drugs, the authors quantitated in normal human cells the suppressive effects of the glucocorticoids prednisolone and methylprednisolone and of cyclosporine on interleukin‐2 (IL‐2) mRNA expression and IL‐2 production, as well as the stimulatory effect of these drugs on IκBα mRNA expression. As expected, cyclosporine was significantly more suppressive than either glucocorticoid of IL‐2 mRNA expression and IL‐2 production by mitogen‐stimulated PBMC, with variable degrees of inhibition in cells from individual subjects. The authors confirmed in human PBMC the stimulation of IκBα mRNA expression by the glucocorticoid reported by others in HeLa and transfected Jurkat cell lines. In addition, the authors observed a stimulatory effect on IκBα mRNA expression by cyclosporine as well in 8 of 10 PBMC preparations studied, suggesting a possible role of calcineurin in the regulation of IκBα a production. Interindividual variability in the intracellular mechanisms of action, possibly based on molecular polymorphisms, might be one factor contributing to differences among patients in their clinical responses to treatment with such drugs.
Lymphocyte Suppression by Glucocorticoids with Cyclosporine, Tacrolimus, Pentoxifylline, and Mycophenolic Acid
Authors: Briggs William A. , Eustace Joseph , Gimenez Luis F. , Choi Michael J. , Scheel Paul J. , Burdick James F.
Published: July 2003

Methylprednisolone has been found to be significantly more suppressive than prednisolone (the pharmacologically active metabolite of prednisone) of mitogen‐stimulated human lymphocyte proliferation. In this study, peripheral blood mononuclear cells (PBMC) from end stage renal disease patients were cultured with phytohemagglutinin (PHA) alone and with methylprednisolone and prednisolone individually, as well as each glucocorticoid (10−7 mol/L) in combination with 300 ng/ml cyclosporine, 10 ng/ml tacrolimus, 25 μg/ml pentoxifylline, and 10−7 mol/L mycophenolic acid. Under each experimental condition, the mean ± SD % inhibition of PHA‐stimulated 3H‐thymidine incorporation was significantly greater with methylprednisolone than with prednisolone: methylprednisolone 55 ± 17 versus prednisolone 28 ± 14, p < 0.001; methylprednisolone + cyclosporine 76 ± 18 versus prednisolone + cyclosporine 52 ± 18, p < 0.001; methylprednisolone + tacrolimus 74 ± 18 versus prednisolone + tacrolimus 50 ± 20, p = 0.001; methylprednisolone + mycophenolic acid 69 ± 14 versus prednisolone + mycophenolic acid 46 ± 15, p < 0.001. These results confirm and extend previous observations and suggest that methylprednisolone might be more effective than prednisone in treatment protocols used to suppress allograft rejection.
Antihyperalgesic Effect of the N‐methyl‐D‐aspartate Receptor Antagonist Dextromethorphan in the Oral Surgery Model
Authors: Gordon Sharon M. , Dubner Ronald , Dionne Raymond A.
Published: July 2003

Peripheral neuronal barrage from tissue injury produces central nervous system hyperexcitability through the activation of N‐methyl‐D‐aspartate (NMDA) receptor sites by excitatory amino acids and neuropeptides. This study evaluated if attenuation of NMDA receptor activation with dextromethorphan (DM) suppresses the postoperative development of hyperalgesia. Seventy‐five patients undergoing oral surgery in a parallel‐group, double‐blind study randomly received either a placebo or the maximally tolerated dose of DM administered orally prior to and continuing for 48 hours following surgery. Pain as measured by category, visual analog, and verbal descriptor scales was not significantly different between groups during the first 6 hours following surgery. However, pain at 48 hours was decreased in the DM group as measured by scales for pain intensity and unpleasantness. Subjects in the DM group also self‐administered fewer acetaminophen tablets for unrelieved pain over 24 to 48 hours postoperatively. The results suggest that DM at maximally tolerated doses does not produce an analgesic effect in the immediate postoperative period but reduces pain at 48 hours. This may be related to antagonism of NMDA receptors necessary for the expression of hyperalgesia associated with noxious afferent input postoperatively.
Pharmacokinetics of Cerivastatin in Renal Impairment Are Predicted by Low Serum Albumin Concentration Rather Than by Low Creatinine Clearance
Authors: Vormfelde Stefan V. , Mück Wolfgang , Freudenthaler Stefan M. , Heyen Petra , Schmage Nikolaus , Kuhlmann Jochen , Müller Gerhard A. , Gundert‐Remy Ursula M. , Gleiter Christoph H.
Published: July 2003

The influence of renal impairment on the clearance of the new HMG‐CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 μg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax, or t1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.
Fosinopril: Pharmacokinetics and Pharmacodynamics in Chinese Subjects
Authors: Ding Philip Y. A. , Chu Kai‐ming , Hu Oliver Yoa‐Pu , Huang Giang‐Ming , Jeng Jing‐Jen , Chang Audrey , Delaney Carol L. , MacAskill Maynard , Yang B. C. , Jemal Mohammed , Smith Robert , Liao Wei‐chi
Published: July 2003

This study examined the pharmacokinetics and pharmacodynamics of fosinopril (IV and oral) in Chinese subjects to determine whether they were different from a group of somewhat heavier and older Western control subjects previously published using the same methods. It was an open‐label, randomized, balanced, two‐way crossover study comparing oral and IV pharmacokinetics in 12 healthy Chinese subjects in a clinic in Taiwan. Each subject received 10 mg of oral fosinopril or 7.5 mg of IV fosinoprilat in a randomized sequence with sampling for fosinoprilat concentrations over 48 hours. Standard pharmacokinetics, including AUC, Cmax, Tmax, T1/2, Vss, bioavailability, total clearance, and renal and nonrenal clearance, were determined as well as pharmacodynamic effects on angiotensin‐converting enzyme (ACE) activity. Following oral administration of 10 mg fosinopril, AUC0‐T and AUCinf were 1556 ± 586 ng • hr/mL and 1636 ± 620 ng • hr/mL, respectively; T1/2 was 17.4 ± 11.4 hr; Cmax was 183.4 ± 59.4 ng/mL; and median Tmax was 4.0 hr, with > 99% protein binding. Following IV administration of 7.5 mg fosinoprilat, AUC0‐T and AUCinf were 7727 ± 2638 ng • hr/mL and 7816 ± 2693 ng • hr/mL, respectively; T1/2 was 13.0 ± 5.2 hr; and median Tmax was 4.0 hr, with 99.5% ± 0.22% protein binding and a Vss of 5850 ± 2780 mL. Bioavailability was 22.3% ± 7.9%. Percent urinary excretion was 7.6% ± 2.6% after oral dosing and 42.6% ± 6.1% after IV dosing. After IV, dosing total clearance was 1088 ± 439 mL/hr, renal clearance was 472 ± 213 mL/hr, and nonrenal clearance was 617 ± 246 mL/hr. ACE inhibition was essentially complete through 12 hours and markedly reduced through 24 hours. Compared to a somewhat heavier and older previously reported control group, pharmacokinetic values were similar except for a slightly lower AUC and total clearance in Chinese and a statistically significantly lower nonrenal clearance. Pharmacodynamic effects on ACE activity were essentially identical. There is no reason to expect significant differences in fosinopril dosing or effect in a Chinese population compared to a Western population.
DHEA and DHEA‐S: A Review
Authors: Kroboth Patricia D. , Salek Firoozeh S. , Pittenger Amy L. , Fabian Tanya J. , Frye Reginald F.
Published: July 2003

Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA‐S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA‐S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA‐S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA‐S concentrations, as well as concentrations of DHEA and DHEA‐S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA‐S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.
Assessment of QTc Prolongation for Non‐Cardiac‐Related Drugs from a Drug Development Perspective
Authors: Bonate Peter L. , Russell Tanya
Published: July 2003

It is increasingly likely that non‐cardiac‐related drugs will need to be routinely analyzed for their ability to prolong cardiac repolarization. This leads to potential problems for drug companies in general and statisticians in particular. A number of issues immediately arise in regard to answering the question, “Does drug X prolong cardiac repolarization?” These include identifying what is the desired outcome, what is the dependent variable, and what analysis method should be used. The purpose of this article is bring to to light some of the issues regarding the analysis of QTc data, the advantages and disadvantages of these analysis methods, and some general recommendations.
Altered Clearance of Theophylline in Children with Down Syndrome: A Case Series
Authors: Stowe Cindy D. , Phelps Stephanie J.
Published: July 2003

Down syndrome (DS) is a common cause of mental retardation resulting from trisomy 21. Previous reports have described altered pharmacokinetics and pharmacodynamics in patients with DS. The authors report six cases of infants (2–19 months) with DS who demonstrated altered theophylline pharmacokinetics. Clearance was prolonged in most of these patients. No overt toxicity to theophylline was noted in any of the cases. The authors propose that patients with DS are at increased risk for altered theophylline pharmacokinetics. The etiology for altered pharmacokinetics of theophylline may be due to the interface between normal developmental changes and pharmacogenetic differences associated with DS and/or the secondary disease states and concomitant drug therapy.
Salivary Clearance and Urinary Metabolic Pattern of Caffeine in Healthy Children and in Pediatric Patients with Hepatocellular Diseases
Authors: El‐Yazigi Adnan , Shabib Souheil , Al‐Rawithi Sameer , Yusuf Ahmed , Legayada Erlinda S. , Al‐Humidan Abdulkarim
Published: July 2003

Measurement of salivary clearance and urinary metabolites of caffeine is an excellent noninvasive tool for assessing liver function, particularly the activity of cytochrome P4501A2 (CYP1A2), N‐acetyltransferase (NAT), and xanthine oxidase (XO). This study was undertaken to measure the clearance of caffeine using saliva as a biological fluid and to assess the activities of the above‐mentioned enzymes in healthy children and pediatric patients with liver diseases using urinary molar ratios of different caffeine metabolites. The well‐established two‐sample saliva approach was used to measure the clearance of caffeine in nine pediatric patients with liver diseases (LD) and in nine healthy children. The caffeine metabolites were also measured in the urine of these subjects by high‐performance liquid chromatography, and urinary molar ratios of 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU), 1‐methylxanthine (1X), 1‐methyluric acid (1U), and 1,7‐dimethyluric acid (17U) were employed to estimate the activities of CYP1A2, NAT, and XO. The caffeine salivary clearance and the percentage of the dose excreted in the form of various metabolites were significantly (p < 0.035) smaller in the LD patients than those in healthy children. The urinary molar ratio of [AFMU + 1U + 1X]/17U, which reflects the activity of CYP1A2, was also significantly (p < 0.0005) reduced in these patients. However, there were no significant differences between the two groups in the ratios of AFMU/1X and 1U/1X, which estimate the activities of NAT and XO, respectively. In conclusion, the data obtained suggest that liver disease in pediatric subjects significantly reduces the salivary clearance of caffeine and the activity of cytochrome P4501A2, but it has no impact on the activities of NAT and XO.
Population Pharmacokinetics of Lamotrigine Adjunctive Therapy in Adults with Epilepsy
Authors: Grasela Thaddeus H. , Fiedler‐Kelly Jill , Cox Eugène , Womble Gilda P. , Risner Marcus E. , Chen Chao
Published: July 2003

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18–64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme‐inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in nonwhites and increased by 13% in patients receiving more than one concomitant enzyme‐inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme‐inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme‐inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.
Pharmacokinetics of Cisplatin Administered by Continuous Hyperthermic Peritoneal Perfusion (CHPP) to Patients with Peritoneal Carcinomatosis
Authors: Cho Hea‐Kyoung , Lush Richard M. , Bartlett David L. , Alexander H. Richard , Wu Peter C. , Libutti Steven K. , Lee Kang Bo , Venzon David J. , Bauer Kenneth S. , Reed Eddie , Figg William D.
Published: July 2003

The pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) was characterized in patients with peritoneal carcinomatosis. Cisplatin was added into the perfusate with escalating doses from 100 mg/m2 to 400 mg/m2. The hyperthermic perfusion was maintained for 90 minutes with a flow rate of 1.5 L/min and a target peritoneal temperature of 42.5°C after a tumor debulking procedure. Samples of both the perfusate and blood were obtained during the perfusion and 30 minutes after the perfusion. Cisplatin plasma and perfusate concentrations were determined by flameless atomic absorption spectrometry with a lower limit of detection of 2 ng/ml and a coefficient of variation (CV) < 10%. Fifty‐six patients were enrolled in the study. The mean (± SD) percentage of cisplatin present in the perfusate at the completion of perfusion was 27.8% ± 20% of the total dose. The maxi mum cisplatin concentrations in the perfusate were 10 times higher than those in plasma. The area under the concentration‐time curve (AUC) of the perfusate was 13 times higher than the AUC of plasma. A two‐compartment model with an additional peritoneal cavity compartment fits to the data best based on the Akaike information criterion. However, the interpatient variability was considerably high (CV < 100%). In conclusion, cisplatin administered by hyperthermic peritoneal perfusion resulted in a pharmacological advantage by obtaining higher and direct drug exposure to the tumor in the peritoneal cavity while limiting systemic absorption and toxicity. Using a complex two‐compartment model, the authors were able to characterize the pharmacokinetics of cisplatin given intraperitoneally via this technique.
Electronic Monitoring of Compliance to Lipid‐Lowering Therapy in Clinical Practice
Authors: Schwed Ariane , Fallab Claire‐Lise , Burnier Michel , Waeber Bernard , Kappenberger Lukas , Burnand Bernard , Darioli Roger
Published: July 2003

Nonadherence to treatment is a common problem in the clinical management of hypercholesterolemic patients. This study was carried out with the aim of monitoring the daily compliance to a 6‐month course of lipid‐lowering therapy, using a microelectronic device, the Medication Event Monitoring System (MEMS™), versus pill count. Forty men with primary hypercholesterolemia were prescribed fluvastatin 1 × 40 mg daily, provided in a MEMS™ package to record the date and time of each opening of the pillbox. Thirty‐nine of 40 patients (98%) completed the study. Total cholesterol and LDL cholesterol levels decreased significantly (18% and 25%, p < 0.001) during the 6‐month therapy period. A high mean rate of compliance was achieved by MEMS™ using the following three indexes—compliance to total prescribed dose (88.8% ± 13.5%), compliance to prescribed days (82.4% ± 19.5%), and compliance to prescribed time of day (81.86% ± 19.5%)—and by pill count (93.4% ± 9.5%). In addition, the MEMS™ provided some patterns of nonadherence to medication, undetectable by pill count alone, such as a drug holiday in 38% of cases, a drug omission for more than 7 consecutive days in 9% of cases, and, conversely, use of more than the one prescribed daily dose in 47% of cases. A significant correlation between the rate of compliance and the decrease in LDL cholesterol was observed only when the compliance was assessed by MEMS™. The results indicate that MEMS™ is a useful tool for monitoring compliance in clinical practice and may possibly increase adherence to long‐term lipid‐lowering therapy.
Effect of Troglitazone on the Pharmacokinetics of an Oral Contraceptive Agent
Authors: Loi Cho‐Ming , Stern Ralph , Koup Jeffrey R. , Vassos Artemios B. , Knowlton Philip , Sedman Allen J.
Published: July 2003

Fifteen healthy women participated in a study to determine the effect of multiple doses of troglitazone on the pharmacokinetics of Ortho‐Novum 1/35 (35 μg ethinyl estradiol [EE] and 1 mg norethindrone [NE]). Participants received three cycles (21 days each of active drug followed by 7 days without medication) of Ortho‐Novum. During the third cycle, participants also received troglitazone 600 mg qd for 22 days. Pharmacokinetic profiles of EE and NE were determined on day 21 of the second and third cycles. Progesterone and sex hormone binding globulin (SHBG) levels were also measured. Troglitazone decreased EE Cmax and AUC(0–24) by 32% and 29%, respectively. Likewise, troglitazone decreased NE Cmax and AUC(0–24) by 31% and 30%, respectively. Plasma SHBG concentrations increased from 113 nmol/L during cycle 2 to 220 nmol/L during cycle 3. Troglitazone reduced plasma unbound AUC for NE by 49%. Serum progesterone levels were lower than 1.5 ng/mL on all occasions. Thus, coadministration of troglitazone and Ortho‐Novum decreases the systemic exposure to EE and NE. A higher dose of oral contraceptive or an alternate method of contraception should be considered for patients treated with troglitazone.
First Time in Human for GV196771: Interspecies Scaling Applied on Dose Selection
Authors: Iavarone L. , Hoke J. F. , Bottacini M. , Barnaby R. , Preston G. C.
Published: July 2003

The utility of interspecies scaling in early drug development has been extensively debated. The authors discuss the dose selection strategy for a first time into man (FTIM) study for GV196771, a new glycine antagonist, using techniques of interspecies scaling. The FTIM dose selection strategy was based on predicted plasma profiles of GV196771 in humans using allometric scaling and considerations of safety and pharmacological activity in animals. Allometric techniques were first retrospectively applied to data obtained in humans and animals for GV150526, a glycine antagonist with similar pharmacokinetic charateristics to GV196771. GV196771 and GV150526 are extensively protein bound; thus, protein binding differences among species were considered in the scaling. Using the scaled pharmacokinetic parameters, compartmental modeling was performed to prospectively simulate concentration profiles for the oral administration of GV196771. This article will discuss the outcome of the prospective dose selection strategy for GV196771 compared to the actual concentration profiles observed in the FTIM study.
Nortriptyline E‐10‐Hydroxylation in Vitro Is Mediated by Human CYP2D6 (High Affinity) and CYP3A4 (Low Affinity): Implications for Interactions with Enzyme‐Inducing Drugs
Authors: Venkatakrishnan Karthik , von Moltke Lisa L. , Greenblatt David J.
Published: July 2003

The human cytochrome P450 (CYP) isoforms mediating nortriptyline 10‐hydroxylation have been identified using kinetic studies on heterologously expressed human CYPs and chemical inhibition studies on human liver microsomes. Nortriptyline was metabolized to E‐10‐hydroxynortriptyline by humanlymphoblast‐expressedCYPs2D6(Km2.1μM) and 3A4 (Km 37.4 μM) with high and low affinity, respectively, whereas CYPs 1A2, 2A6, 2B6, 2C9, 2C19, and 2E1 had no detectable activity. Human liver microsomal nortriptyline E‐10‐hydroxylation displayed biphasic kinetics. The high‐affinity component (Km 1.3 ± 0.4 μM, n = 11 livers) was selectively inhibited by the CYP2D6 inhibitor quinidine, whereas the CYP3A4 inhibitor ketoconazole selectively inhibited the low‐affinity component (Km 24.4 ± 7 μM, n = 11 livers). Inhibition by ketoconazole increased with increasing substrate concentration, whereas the reverse was true for quinidine. The Vmax of the low‐affinity component in human liver microsomes was significantly correlated (r2 = 0.84) with the relative activity factor for CYP3A4, a measure of the amount of catalytically active enzyme. A simulation of the relative contribution of CYPs 2D6 and 3A4 to net nortriptyline hydroxylation rate suggested that the relative contribution of CYP3A4 is only 20% even at the higher end of the therapeutic range. Induction of CYP3A4 will increase its importance and increase the net metabolic rate, whereas inhibition of CYP3A4 will be of little importance due to its minimal relative contribution under uninduced conditions. The identification of CYP3A4 as a low‐affinity nortriptyline E‐10‐hydroxylase explains the ability of poor metabolizers of debrisoquin to hydroxylate nortriptyline, as well as the increased in vivo clearance via this pathway caused by CYP3A4‐inducing drugs such as pentobarbital, carbamazepine, and rifampin.
Differences in the Urinary Excretion of 6‐β‐Hydroxycortisol/Cortisol between Asian and Caucasian Women
Authors: Lin Yixin , Anderson Gail D. , Kantor Eric , Ojemann Linda M. , Wilensky Alan J.
Published: July 2003

The urinary ratio of6‐β‐hydroxycortisol/cortisol has been used as a noninvasive probe for human cytochrome P450 3A4 isoforms (CYP3A4). Ethnic‐related differences in the ratio have not been evaluated. The aim of this study was to determine if there are differences in the ratio between Asian and Caucasian women over a menstrual cycle. First‐morning urine samples were collected every other day starting from the second day of menstruation for a complete menstrual cycle from 15 Asians and 16 Caucasian women who were 18 to 40 years old, healthy nonsmoking, and alcohol and drug free, including oral contraceptives. Urine concentrations of 6‐β‐hydroxycortisol and cortisol were measured by high‐pressure liquid chromatography (HPLC). For statistical analysis, three phases of the menstrual cycle were evaluated: menstruation (days 1–4), follicular or postmenstruation (days 6–10), and the luteal phase (days 21–24) based on the average menstrual cycle (28 days). Statistical analysis was performed by an independent sample t‐test using the Bonferroni correction for repeated measures. Large intersubject and intrasubject variations of the 6‐β‐hydroxycortisol/cortisol ratios were observed during the menstrual cycles in both ethnic groups. Asian women had a statistically significant lower ratio than Caucasian women did for all three phases of the menstrual cycle: 2.2 ± 1.1 versus 5.1 ± 3.5, 2.1 ± 1.1 versus 6.0 ± 4.9, and 2.8 ± 1.6 versus 5.6 ± 3.0 for the menstruation, follicular, and luteal phases, respectively. The two‐ to threefold lower 6‐β‐hydroxycortisol/cortisol ratios in Asian women suggest that Asian women may have a lower CYP3A activity compared with Caucasian women. Differences in ethnicity may mask potential gender‐related effects if ethnic background is not evaluated as a contributing factor.
Pharmacokinetic and Pharmacodynamic Analysis of Subcutaneous Recombinant Human Granulocyte Colony Stimulating Factor (Lenograstim) Administration
Authors: Hayashi Naoto , Kinoshita Haruki , Yukawa Eiji , Higuchi Shun
Published: July 2003

A total of 72 adult healthy volunteers were administered 1 μg/kg of rhG‐CSF. There was no correlation between Cmax and an increase in peripheral neutrophil count, and there was a negative correlation between AUC and this increase. The mechanism of this is probably based on the correlation between the elimination rate constant (ke) and neutrophil increase. The ke probably has a close relationship with uptake by neutrophil and its progenitor via the G‐CSF receptor. An individual with higher ke should therefore show a greater increase in neutrophil count. Therefore, AUC is proportional to the rhG‐CSF remainder, that is, the proportion that is not consumed in the course of increasing the neutrophil count. In such a situation, the bioavailability calculated from the AUC is unlikely to indicate the absorbed amount. The authors also analyzed the pharmacokinetics using a two‐compartment model with zero‐order absorption and first‐order elimination. This model was sufficient to obtain a good curve fit, and this demonstrates that the absorption process is not a first‐order but a zero‐order process. Therefore, there might be an upper limit to the rhG‐CSF transfer rate from subcutaneous tissue to blood.
Feasibility and Functionality of OROS® Melatonin in Healthy Subjects
Authors: Shah Jaymin , Langmuir Virginia , Gupta Suneel K.
Published: July 2003

OROS® (melatonin), an oral osmotic system for controlled drug delivery, was evaluated in an open‐label, two‐way crossover study to test the feasibility of continuous overnight melatonin delivery. Twelve healthy subjects with no sleep disorders, ranging from 60 to 73 years of age, were enrolled in the study. Two doses of melatonin (1 × 110 μg and 4 × 110 μg) were administered on two separate occasions. Endogenous baseline nighttime serum melatonin concentrations were measured the night before each treatment. Following treatment at 2100 hours, the lights were extinguished at 2200 hours and remained so, except during blood sample collection, which was performed under dim light (< 50 lux) at specified times. Serum samples were analyzed for melatonin by an LC/MS/MS method. In addition, safety measurements such as vitals and serum samples for endocrine functions were measured both prior to and after melatonin dosing. The serum melatonin concentration profile following OROS® (melatonin) dosing mimicked the normal endogenous serum melatonin concentration‐time profile. The mean maximal melatonin concentration occurred at 3 a.m. The mean AUCs of endogenous melatonin before the two treatment days were 248 and 234 pg•h/mL, respectively. Serum concentrations of melatonin corrected for endogenous production increased proportionally with dose, with AUCs of 288 and 1069 pg•h/mL, respectively. Deconvolution of the serum concentration data showed good correlation between the in vitro amount released and the in vivo amount absorbed, suggesting continuous absorption throughout the gastrointestinal tract. Less than 5% residual content was observed in the recovered OROS® system. Minimal changes in serum hormone concentrations (luteinizing hormone, follicular stimulating hormone, and prolactin) and no serious adverse events were observed following OROS® treatment in these subjects. Delivery of melatonin with OROS® formulation may result in a physiologic nocturnal profile in elderly subjects.
Clozapine and Metabolite Concentrations during Treatment of Patients with Chronic Schizophrenia
Authors: Guitton Claire , Kinowski Jean‐Marie , Abbar Mocrane , Chabrand Pierre , Bressolle Françoise
Published: July 2003

Results presented in this article are focused on the variability in pharmacokinetics. The purpose of this study was (1) to investigate intra‐ and interindividual variabilities of pharmacokinetic parameters of clozapine and its two main metabolites in plasma after multiple oral administration in 8 chronic schizophrenic patients (Study 1) and (2) to gain more information regarding plasma concentrations of these drugs after multiple doses in a group of 25 treatment‐responsive patients (Study 2). Patients were treated with clozapine in fixed daily doses (given every 8–12 hours) between 200 and 900 mg. Plasma drug concentrations were determined by high‐performance liquid chromatography. The mean volume of distribution and the total plasma clearance of clozapine, uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The terminal elimination half‐lives averaged 10.5 hours for clozapine, 19.2 hours for norclozapine, and 8.6 hours for the N‐oxide metabolite. Significant relationships were observed between clozapine and norclozapine (or clozapine N‐oxide) plasma concentrations. Large inter‐ and intrapatient variations in pharmacokinetics were observed. Clozapine was generally well tolerated by the patients, with sedation, hypersialorrhea, and tiredness as the most common side effects encountered.
Pharmacokinetic and Pharmacodynamic Action of Etodolac in Patients after Oral Surgery
Authors: Boni Joseph , Korth‐Bradley Joan , McGoldrick Karen , Appel Alan , Cooper Stephen
Published: July 2003

The objective of this double‐blind, randomized, parallel‐group study was to evaluate the pharmacokinetics of etodolac and the pharmacodynamic response of pain in patients following oral surgery who had received 200 or 400 mg of etodolac immediate release (IR), 400 or 1200 mg of etodolac extended release (ER), or a placebo. Etodolac concentrations in 441 plasma samples from 187 patients were analyzed for population pharmacokinetics using the NONMEM program. A one‐compartment pharmacokinetic model with first‐order absorption described the observed data. For etodolac IR, the population mean (%CV) estimates were 3.01 L/h (5.3%) for clearance, 13.6 L (6.8%) for volume of distribution, and 2.31 h−1 (33%) for ka. Respective values for etodolac ER were 3.68 L/h (11%) for clearance, 24.3 L (22%) for volume of distribution, and 0.172 h−1 (24%) for ka. These values generally agreed with previously reported values in healthy adults. Pharmacodynamic assessments included collection of a four‐level categorical rating of pain intensity for up to 24 hours after treatment. Pain intensity difference scores were temporally related to etodolac concentrations and were described using an indirect response model. Mean (%CV) pharmacodynamic parameters were IC50 of 14.0 mg/L (9.5%), kout of 1.62 h−1 (13%), FR of 0.56 (8.2%), and Hill coefficients that ranged from 1.26 to 3.34 units. A single 1200 mg dose of etodolac ER given once daily was shown to provide substantial efficacy for 13 hours after dose, modest effect through 24 hours, and a more sustained duration of action than the IR dosage form.
Developments in the Therapeutic Applications of Bisphosphonates
Authors: Brown Darwin L. , Robbins Richard
Published: July 2003

The authors review the structural, pharmacologic, and clinical aspects of bisphosphonates, a class of drugs currently used to treat several disorders of bone and calcium metabolism. Pertinent literature on the bisphosphonates was reviewed with the help of a MEDLINE search and several bibliographies, including published clinical trials, monographs, and review articles. The bisphosphonates are analogs of pyrophosphate that, when given orally or intravenously, bind avidly to exposed bone mineral and disrupt bone turnover. These agents comprise three groups or generations, based on their potency and chemical structures. All three generations are effective in treating hypercalcemia, Paget's disease of bone, osteoporosis, and other disorders of accelerated bone turnover. The third‐generation agents have the greatest potency and offer the promise of a convenient way to suppress or prevent osseous metastasis in patients with certain malignancies. As a group, these agents are well tolerated and, when administered correctly, rarely cause toxicity. The bisphosphonates are safe and effective agents for the treatment of disorders of accelerated bone turnover.
Absolute Oral Versus Inhaled Bioavailability: Significance for Inhaled Drugs with Special Reference to Inhaled Glucocorticoids
Authors: Rohatagi Shashank , Rhodes Gerald R. , Chaikin Philip
Published: July 2003

Orally inhaled drugs provide great benefit in the treatment of asthma as they are delivered directly to the site of action, i.e. the lung. The absolute oral inhaled bioavailability of a glucocorticoid results from the combination of the bioavailability of the dose delivered to the lung and the bioavailability of the dose delivered into the gastrointestinal (GI) tract. The majority of the dose delivered to the lung is absorbed and available systemically. For the portion of the glucocorticoid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass/pre‐systemic metabolism in the GI tissue and liver. Since this oral component of the delivered dose does not provide any beneficial therapeutic effect but can contribute to the systemic side effects, it is desirable for the absolute oral bioavailability of inhaled glucocorticoids to be relatively low (which is the case with most of the glucocorticoids, < 25%). Another approach to limiting systemic exposure from inhaled delivery is to improve the effectiveness of the oral inhaled formulation and delivery device, by increasing the fraction of the total inhaled dose which reaches the lung. Since current inhalation technology can provide respirable fractions in the range of 30–50%, what is the significance of the oral component of systemic exposure in relation to the overall systemic exposure following the oral inhalation administration of glucocorticoids? Below a certain point (<25%), lower oral bioavailability of inhaled drugs may not be clinically important with respect to systemic exposure if the lung targeting is good (30%).
Intraindividual Variability in Male Hepatic CYP3A4 Activity Assessed by Alfentanil and Midazolam Clearance
Authors: Kharasch Evan D. , Jubert Carole , Senn Tauri , Bowdle T. Andrew , Thummel Kenneth E.
Published: July 2003

Clinical investigations using isoform‐selective probes to phenotype cytochrome P450 activity and interaction studies using isoform‐selective inhibitors to determine P450 involvement in drug metabolism assume minimal interday variability in P450 activity. CYP3A4 is the most abundant human P450 isoform and metabolizes approximately half of all therapeutic agents. This investigation evaluated interday variability in hepatic CYP3A4 activity in males, using the clearances of midazolam and alfentanil as metabolic probes. Midazolam (1 mg) followed 1 hour later by alfentanil (20 μg/kg) were administered by intravenous bolus to 9 nonsmoking male volunteers (ages 30 8 years). Drug administration was repeated 12 and 20 days later. Venous plasma midazolam and alfentanil concentrations were determined by gas chromatography/mass spectrometry. Drug clearances were determined by noncompartmental and multiexponential analysis. There were no significant interday differences in plasma drug concentrations or clearances (3.9 1.4, 3.9 1.7, and 4.2 1.7 ml/kg/min for alfentanil, respectively, and 6.6 2.0, 7.9 2.4, and 7.9 2.5 ml/kg/min for midazolam, respectively, on days 1, 13, and 21 [mean SD]). Interday variability in clearance was 13% 6% and 19% 12% for alfentanil and midazolam, respectively. Interday variability in the clearance of these probes, and presumably hepatic CYP3A4 activity, was small compared with interindividual variability. Consideration of interday variability in the hepatic metabolism of CYP3A4 substrates does not appear significant in the design of clinical trials.
Rapid Disappearance of Zaleplon from Breast Milk after Oral Administration to Lactating Women
Authors: Darwish Mona , Martin Patrick T. , Cevallos William H. , Tse Susanna , Wheeler Sarah , Troy Steven M.
Published: July 2003

Five lactating mothers were administered the therapeutic dose of zaleplon (10 mg) orally in an open‐label, single‐dose, pharmacokinetic study. Plasma and breast milk were sampled through 8 hours after dose administration for subsequent determinations of zaleplon and its major, though inactive, plasma metabolite 5‐oxo‐zaleplon. Zaleplon concentrations peaked in plasma and milk approximately 1 hour after dosing and then disappeared rapidly. The mean terminal half‐life was slightly greater than 1 hour. Milk concentrations “mirrored” plasma concentrations closely with no discernible delay between peak times. The average milk‐to‐plasma (M/P) concentration ratio for zaleplon was approximately 0.50 over the time course. 5‐oxo‐zaleplon was undetectable in all but one milk sample. The maximum exposure of an infant to zaleplon during a feeding at peak milk concentrations was estimated to range from 1.28 μg to 1.66 μg, corresponding to 0.013% to 0.017% of the maternal dose or 0.320 μg/kg to 0.415 μg/kg for a 4 kg infant. The results indicate that zaleplon taken by a nursing mother is transferred through breast milk to her infant in very small quantities that are unlikely to be clinically important.
Multiple‐Dose Pharmacokinetics, Safety, and Tolerability of Bosentan, an Endothelin Receptor Antagonist, in Healthy Male Volunteers
Authors: Weber Cornelia , Schmitt Rita , Birnboeck Herbert , Hopfgartner Gerard , Eggers Herwig , Meyer Joseph , van Marle Sjoerd , Viischer Henk W. , Jonkman Jan H. G.
Published: July 2003

The multiple‐dose pharmacokinetics, safety, and tolerability of oral bosentan, a selective endothelin receptor antagonist, were investigated in healthy male volunteers. In study A, an ascending‐dose, double‐blind, placebo‐controlled trial, doses of 100, 200, 500, and 1000 mg bosentan or placebo were given once daily for 8 days as tablets (100 and 500 mg dose strength). In study B, a double‐blind, placebo‐controlled trial, 500 mg tablets of bosentan or placebo tablets were given once daily for 8 days with two additional single intravenous dose administrations of 250 mg bosentan 48 hours before the first and 24 hours after the last oral dose. The drug was very well tolerated. No effects on pulse rate, ECGs, or clinical laboratory tests were observed. Marginal effects on blood pressure were seen in subjects only when standing. The oral bioavailability of bosentan was 43% to 48%, with a small interindividual variability of 20%. Doses above 500 mg did not lead to significant further increases in plasma levels of bosentan. From the first to the last day of the oral treatment phase, plasma concentrations of bosentan decreased by 30% to 40% due to a 2‐fold increase in plasma clearance. Absorption and plasma protein binding did not change. The 24‐hour urinary excretion of 6β‐hydroxycortisol was increased in parallel by approximately 1.7‐fold, indicating induction of cytochrome P450 3A isozymes. The two metabolites of bosentan reached plasma concentrations well below those of bosentan and will most likely not contribute to the pharmacological activity.
The Effect of Renal Insufficiency on Mycophenolic Acid Protein Binding
Authors: Kaplan Bruce , Meier‐Kriesche H. U. , Friedman Gary , Mulgaonkar Shamkant , Gruber Scott , Korecka Magda , Brayman Kenneth L. , Shaw Leslie M.
Published: July 2003

Mycophenolate mofetil (MMF) is commonly used in solid organ transplant recipients. MMF is converted to mycophenolic acid (MPA) upon reaching the systemic circulation. Many acidic drugs have altered protein binding in renal failure, and it is possible that MPA protein binding may be decreased. The authors studied 23 renal transplant recipients: 8 transplant patients (7 kidney, 1 kidney/pancreas) with chronic renal insufficiency (CRI) and 15 renal transplant patients with preserved renal function. Plasma was obtained for kinetic profiles of total MPA, free MPA, and its glucuronide metabolite (MPAG). Plasma was obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess in vitro differences in MPA protein binding. Average free fraction of MPA in patients with chronic renal insufficiency was more than double that of patients with normal renal function (5.8 2.7 vs. 2.5 0.4, p < 0.01). Free MPA AUC was almost doubled in the patients with chronic renal insufficiency versus controls (2.04 .08 vs. 1.03 0.6, p < 0.01). MPA protein binding is decreased, and free MPA concentrations are increased in patients with chronic renal failure.