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1.
Aliment Pharmacol Ther ; 30(3): 301-6, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19459829

ABSTRACT

BACKGROUND: Oral tablet formulations of metoclopramide are effective therapies for gastroparesis and gastro-oesophageal reflux disease; however, difficulty swallowing tablets or nausea/vomiting may reduce patient adherence to therapy. Because of this, a metoclopramide orally-disintegrating tablet (ODT) has been developed. AIM: To evaluate the bioequivalence of a single administration of a 10-mg metoclopramide ODT and a conventional 10-mg oral metoclopramide tablet in healthy volunteers. METHODS: In a randomized, single-dose, crossover study, healthy volunteers received single administration of 10-mg metoclopramide ODT and 10-mg conventional metoclopramide tablet, with a 7-day interval between treatments. Serial blood samples were collected before dosing and during 24 h post-treatment. RESULTS: Forty-one volunteers completed both treatment arms. Metoclopramide ODT was bioequivalent to conventional tablets; 90% CIs for geometric mean treatment ratios of C(max) [91.6% (90% CI, 87.7-95.8%)], AUC(last) [97.3% (90% CI, 94.5-100.2%)] and AUC(inf) [97.6% (90% CI, 94.5-100.8%)] were within the predefined range. Of the 44 volunteers included in the safety analysis, 9 (20%) reported AEs after ODT, compared with 13 (30%) after conventional tablets. CONCLUSION: In healthy volunteers, single administration of 10-mg metoclopramide ODT was well tolerated and bioequivalent to single administration of a conventional 10-mg metoclopramide tablet.


Subject(s)
Deglutition Disorders , Gastroesophageal Reflux/drug therapy , Metoclopramide/pharmacokinetics , Tablets , Administration, Oral , Adolescent , Adult , Cross-Over Studies , Female , Humans , Male , Medication Adherence , Metoclopramide/administration & dosage , Middle Aged , Therapeutic Equivalency , Young Adult
2.
Int J Clin Pharmacol Ther ; 45(7): 418-22, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17725249

ABSTRACT

Rifalazil, a second-generation rifamycin, is being evaluated for the treatment of sexually transmitted disease and gastrointestinal infections. We determined whether rifalazil influences CYP3A4 metabolism by studying the effect of a single oral, 25 mg dose of rifalazil administered to healthy postmenopausal women, on the steady-state pharmacokinetics (PK) of ethinyl estradiol (EE) during administration of Ortho-Novum 1/35 (EE/NET). Noncompartmental PK and sequential statistical analyses were performed to establish if and when subjects achieved steady-state EE plasma concentrations and to determine whether this steady state was altered by rifalazil administration. The geometric mean ratios for the difference between EE alone and following rifalazil for EE Cmax, AUC(0-24) and Cmin were 105.9, 104.4 and 105.0, respectively. The 90% confidence intervals for each ratio fell within 80 - 125% of the reference treatment indicating no significant difference in the PK of EE before or after rifalazil administration. The posterior probabilities for the true treatment differences of Cmax or AUC(0-24) being less than 20% were > 99.99% in both cases. Based on the results of this study, there is no CYP3A4-metabolic interaction between a single oral, 25 mg dose of rifalazil and EE for either induction or inhibition. Consequently, there is minimal threat of contraceptive failure when single doses of rifalazil are administered with EE/NET. A single dose of rifalazil 25 mg was well tolerated when administered concomitantly with a combination oral contraceptive (EE/NET) by healthy postmenopausal females.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Estrogens/pharmacokinetics , Ethinyl Estradiol/pharmacokinetics , Rifamycins/administration & dosage , Drug Interactions , Estrogens/blood , Ethinyl Estradiol/blood , Female , Humans , Middle Aged , Postmenopause
3.
J Pharm Biomed Anal ; 31(5): 937-51, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12684106

ABSTRACT

Roxifiban (DMP 754) is a glycoprotein (GP) IIb/IIIa antagonist. Following oral administration to humans, roxifiban is metabolized to its primary active zwitterionic form, XV459, and several minor, active, hydrolyzed and hydroxylated metabolites, namely, M1a (DPC-AD3508), M1b (DPC-AD6128), M2 (SW156), M3 (DPC-AG2185), M8a (DPC-AF5814), and M8b (DPC-AF5818). Quantification of these metabolites in humans was not workable with a previous analytical method due to ion suppression of at least four of the analytes by a competitive displacer, DMP 728. This compound, which is another GP IIb/IIIa antagonist with very high affinity for the platelet receptor, was added to harvested blood samples in millimolar quantity to liberate XV459 from the GP IIb/IIIa receptor. An automated ion exchange solid phase extraction (IX-SPE) procedure was developed to selectively extract the seven metabolites of roxifiban and its deuterated internal standard while specifically excluding DMP 728. Among the six hydroxylation metabolites, there were two pairs of epimeric diastereomers (M1a/M1b and M8a/M8b) and one pair of geometric isomers (M2/M3), corresponding to three critical chromatographic pairs that needed to be base-line resolved because of the lack of specificity of MS/MS detection for these isomers. A new LC/MS/MS assay was developed to simultaneously quantify the seven metabolites in human plasma. The assay method was validated under GLP conditions over the concentration range of 0.5 to 80 nM for each of the analytes and successfully applied to assaying approximately 500 plasma samples from clinical trials.


Subject(s)
Amidines/blood , Isoxazoles/blood , Mesylates/blood , Peptides, Cyclic/blood , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Amidines/metabolism , Calibration , Chromatography, High Pressure Liquid/methods , Humans , Isoxazoles/metabolism , Mass Spectrometry/methods , Reproducibility of Results
4.
Int J Clin Pharmacol Ther ; 40(11): 507-19, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12698988

ABSTRACT

A population-based pharmacokinetic (PK) model has been developed for efavirenz based on 16 phase I studies. The combined data set consisted of 334 healthy volunteers, 2,907 efavirenz dose administrations and 9,342 measured plasma concentrations across a range of doses from 100-600 mg. The pharmacokinetic structural model was a 2-compartment model with first-order absorption with differentiation between single- and multiple-dose exposure to account for known hepatic cytochrome P450 induction of efavirenz metabolism. Model-building was performed on the index data set (66% of the total database), as a data-splitting technique was used to validate the final model using NONMEM. The final model confirmed the appropriateness of separate clearance terms for single and multiple dose administration (2.65 versus 10.2 l/h, respectively). Clearance increased with dose and frequency of administration. A lower clearance was predicted in Asians and Blacks relative to Caucasians. A slightly lower clearance was observed in females relative to males (9.08 compared to 10.2 l/h in males) and interactions on clearance due to co-administration of fluconazole, ritonavir, rifampin, indinavir and azithromycin were identified. The magnitudes of these effects were small and did not suggest dose adjustment in the various subpopulations. With little exception, these results agree with the findings from the non-compartmental analyses. The residual variability was 21% CV and the intersubject variation in CL/F and V/F was 48 and 85%, respectively. The phase I meta-analysis was able to substantiate the pharmacokinetic characteristics of efavirenz derived from the composite of individual well-defined studies. The model was deemed adequate for subsequent evaluation in HIV-infected patients. Covariates and outlier classes identified in this phase I meta-analysis were similarly identified in subsequent analyses of patient data.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Oxazines/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Administration, Oral , Adult , Alkynes , Anti-HIV Agents/blood , Area Under Curve , Benzoxazines , Clinical Trials, Phase I as Topic , Cyclopropanes , Dose-Response Relationship, Drug , Drug Interactions , Female , HIV Infections/drug therapy , HIV Infections/metabolism , HIV Reverse Transcriptase/antagonists & inhibitors , Humans , Male , Models, Biological , Models, Statistical , Oxazines/blood
6.
Thromb Res ; 101(4): 243-54, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11248285

ABSTRACT

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism in conjunction with warfarin for the prevention of DVT in patients undergoing hip or knee replacement surgery, and as an anticoagulant in hemodialysis circuits. Its average molecular weight ranges between 5500 and 7500 daltons (Da); the percentage of chains with molecular weight lower than 2000 Da is not more than 10% in the marketed tinzaparin formulation. While this fraction is generally considered pharmacologically inactive, this has never been evaluated in vivo. The importance of the < 2000 Da fraction on the anticoagulant pharmacodynamics of tinzaparin assessed by anti-Xa and anti-IIa activity was studied in a two-way crossover trial. In this trial, 30 healthy volunteers received a single 175 IU/kg subcutaneous administration of tinzaparin containing approximately 3.5% of the < 2000 Da fraction and a tinzaparin-like LMWH containing 18.3% of the < 2000 Da fraction. The anti-Xa/anti-IIa ratios of the drug substances were comparable at 1.5 and 1.7 for tinzaparin and the tinzaparin-like LMWH, respectively. Both formulations were safe and well tolerated. Mean maximum plasma anti-Xa activity (A(max)) was approximately 0.818 IU/ml at 4 h following tinzaparin injection. Mean maximum plasma anti-IIa activity was 0.308 IU/ml at 5 h postdose. Intersubject variation was lower (< 18% for both anti-Xa and anti-IIa metrics) than in previous fixed-dose administration studies. There was no correlation between anti-Xa or anti-IIa AUC or A(max) and bodyweight in the present study supporting the weight-adjusted dosing regimen. Individual anti-Xa and anti-IIa profiles following the single 175 IU/kg subcutaneous administration of the tinzaparin-like LMWH were similar to that obtained with tinzaparin. Based on average equivalence criteria, the two LMWH preparations were determined to be bioequivalent using either anti-Xa or anti-IIa activity as biomarkers. The calculated intrasubject variabilities were low (< 14% for anti-Xa activity and < 18% for anti-IIa activity) yielding little evidence for a significant Subject x Formulation interaction. In summary, anti-Xa and anti-IIa activity following a single subcutaneous administration of tinzaparin 175 IU/kg to healthy volunteers yielded activity consistent with targeted therapeutic levels derived from previous trials in adult DVT patients. Weight-based dosing for the treatment of DVT appears rational based on the reduction in anti-Xa and anti-IIa variability consistent with the recommendation derived from earlier fixed-dose pharmacokinetic studies. Furthermore, differences in the percentage of molecules in the < 2000 Da molecular weight fraction of tinzaparin do not translate into differences in anti-Xa and anti-IIa activity in vivo.


Subject(s)
Anticoagulants/pharmacology , Heparin, Low-Molecular-Weight/pharmacology , Adult , Anticoagulants/administration & dosage , Anticoagulants/chemistry , Carbohydrate Sequence , Cross-Over Studies , Factor Xa Inhibitors , Female , Heparin, Low-Molecular-Weight/administration & dosage , Heparin, Low-Molecular-Weight/chemistry , Humans , Injections, Subcutaneous , Male , Middle Aged , Molecular Sequence Data , Molecular Weight , Prothrombin/antagonists & inhibitors , Safety , Therapeutic Equivalency , Tinzaparin
7.
Drug Metab Dispos ; 29(2): 96-9, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11159796

ABSTRACT

Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of [14C]losoxantrone for a total dose of 50 mg/m(2) during the first course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug. In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors.


Subject(s)
Anthraquinones/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Neoplasms/metabolism , Pyrazoles/pharmacokinetics , Pyrazolones , Anthraquinones/administration & dosage , Anthraquinones/blood , Anthraquinones/urine , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Antineoplastic Agents/urine , Carbon Radioisotopes , Feces , Humans , Infusions, Intravenous , Neoplasms/blood , Neoplasms/drug therapy , Neoplasms/urine , Pyrazoles/administration & dosage , Pyrazoles/blood , Pyrazoles/urine
8.
Xenobiotica ; 29(9): 945-55, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10548454

ABSTRACT

1. The metabolism of moricizine.HCl was studied in 12 male volunteers dosed with 250 mg (300 microCi) 14C-radiolabelled drug. 2. Moricizine was biotransformed to many metabolites in humans (at least 35 plasma and 51 urine metabolites). 3. Urine and faecal combined mean (range) recovery accounted for 90.2% (73.4-101.6%) of the administered radioactivity, with most of the recovered radioactivity present in faeces (mean 58.4%; range 45.6-64.7%). Mean (range) urinary recovery was 31.8% (26.2-36.9%), with <1% of the dose recovered as intact moricizine, and no one metabolite accounting for >2.5% of the dose. 4. Total radioactivity (TR) plasma t1/2 was 85.2 h, while that for moricizine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 23.6 h. The largest portion (11%) of TR AUC (area under the plasma concentration-time curve) was attributed to 2amino-10-glucuronophenothiazine. Each of the other metabolites accounted for less of the TR AUC than parent drug except for two unidentified peaks which had comparable areas (approximately 5% of the total radioactivity area). 5. Two identified moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, possess the structural characteristics proposed for class 1 anti-arrhythmic activity (pendant amine functionality) and have plasma half-lives 4-7-fold longer than moricizine.


Subject(s)
Anti-Arrhythmia Agents/blood , Anti-Arrhythmia Agents/urine , Moricizine/blood , Moricizine/urine , Adult , Anti-Arrhythmia Agents/pharmacokinetics , Carbon Radioisotopes , Half-Life , Humans , Male , Middle Aged , Moricizine/pharmacokinetics , Reference Values
9.
J Clin Pharmacol ; 39(8): 817-25, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10434234

ABSTRACT

The relative bioavailability of a 200 mg film-coated tablet of [12C]moricizine.HCl in comparison to a 200 mg [13C6]moricizine.HCl oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine.HCl and [13C6]moricizine.HCl were determined by thermospray liquid chromatography-mass spectrometry (LC-MS) using [2H11]moricizine.HCl as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (%CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) microgram/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration-time curve (AUC), 1.58 (39%) versus 1.49 (37%) micrograms.h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t1/2, 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first-pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cv epsilon) afforded via the single-period, dual-isotope design. In contrast, a previous study using the conventional two-period crossover design determined the cv epsilon about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this study further illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design.


Subject(s)
Anti-Arrhythmia Agents/pharmacokinetics , Moricizine/pharmacokinetics , Adult , Anti-Arrhythmia Agents/adverse effects , Area Under Curve , Biological Availability , Carbon Isotopes , Cross-Over Studies , Fatigue/chemically induced , Gastrointestinal Diseases/chemically induced , Humans , Hydrogen , Isotopes , Male , Metabolic Clearance Rate , Moricizine/adverse effects , Moricizine/blood , Nausea/chemically induced , Pharmaceutical Solutions , Pilot Projects , Tablets, Enteric-Coated , Therapeutic Equivalency
10.
Biopharm Drug Dispos ; 20(6): 309-18, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10701702

ABSTRACT

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H-SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 microg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 microg/mL was obtained at the 2.0 microg/kg dose. Pooling individual concentration-time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half-life of 2.8 h in the guinea pig at the 0.5 microg/kg dose. The 2.0 microg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non-plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists.


Subject(s)
Amino Acids/pharmacokinetics , Isoxazoles/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Amino Acids/blood , Amino Acids/pharmacology , Animals , Area Under Curve , Binding Sites/drug effects , Binding, Competitive/drug effects , Guinea Pigs , Humans , Infusions, Intravenous , Isoxazoles/blood , Isoxazoles/pharmacology , Male , Metabolic Clearance Rate , Platelet Aggregation Inhibitors/blood , Platelet Aggregation Inhibitors/pharmacology , Species Specificity , Structure-Activity Relationship
11.
J Pharm Biomed Anal ; 17(3): 427-34, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9656154

ABSTRACT

A simple, specific, and sensitive high-performance liquid chromatographic (HPLC) assay utilizing ultraviolet (UV) detection for the determination of bisnafide in human plasma was developed, validated, and applied to plasma samples from patients undergoing cancer therapy. Plasma samples, containing an internal standard, XE842, were first deproteinized with 2.0 ml acetonitrile, and subsequently, 1.0 ml and pH 9 boric acid-potassium chloride-sodium hydroxide buffer (0.1 M) was added. To this mixture, 9.0 ml of ethyl ether was added then vortex mixed. Following centrifugation, the ether layer was back-extracted into 250 microliters of 0.1 M phosphoric acid, then removed by vacuum aspiration. A portion of the remaining acid layer was directly injected onto the HPLC. Bisnafide was quantified using a Shiseido Capcell Pak C8 HPLC column and ultraviolet detection (274 nm). The lower limit of quantification was 10 ng ml-1 using 1.0 ml plasma. The intraday precision (RSD) ranged from 2.7 to 8.6% over a concentration range of 10-1000 ng ml-1. The interday precision (RSD) ranged from 5.6 to 11.5%. Overall mean accuracy was +/- 5.2%. The drug was stable in frozen heparinized human plasma stored at -20 degrees C for at least 1 year and stable throughout at least two freeze-thaw cycles. This method was successfully utilized for quantifying plasma concentrations needed to study the clinical pharmacokinetics of bisnafide in patients undergoing cancer therapy.


Subject(s)
Antineoplastic Agents/blood , Chromatography, High Pressure Liquid/methods , Isoquinolines/blood , Mesylates/blood , Antineoplastic Agents/pharmacokinetics , Calibration , Drug Stability , Humans , Isoquinolines/pharmacokinetics , Mesylates/pharmacokinetics , Neoplasms/blood , Spectrophotometry, Ultraviolet , Time Factors
12.
Ann Oncol ; 9(1): 101-4, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9541690

ABSTRACT

PURPOSE: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. PATIENTS AND METHODS: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. RESULTS: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25-86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P < 0.01, Wilcoxon Rank Sum test). CONCLUSION: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.


Subject(s)
Antineoplastic Agents/therapeutic use , Isoquinolines/therapeutic use , Mesylates/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Half-Life , Hematologic Tests , Humans , Infusions, Intravenous , Isoquinolines/adverse effects , Isoquinolines/pharmacokinetics , Mesylates/adverse effects , Mesylates/pharmacokinetics , Middle Aged
13.
Xenobiotica ; 27(2): 217-29, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9058534

ABSTRACT

1. Using synthetic standards and/or spectral data, seven moricizine metabolites were structurally identified in human urine. Two novel metabolites were identified as phenothiazine-2-carbamic acid and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate. Two novel human moricizine metabolites, 2-amino-10-(3-morpholino-propionyl) phenothiazine, a previously identified dog metabolite, and 2-aminophenothiazine, a previously identified rat metabolite, were also identified. Three additional human metabolites, phenothiazine-2-carbamic acid ethyl ester sulphoxide (P2CAEES), moricizine sulphoxide, and ethyl ¿10-[N-(2'-hydroxyethyl)3-aminopropionyl] phenothiazin-2-yl¿ carbamate, all previously described in the literature, were observed. 2. Both 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, and possibly ethyl ¿10-[N-(2'-hydroxyethyl) 3-aminopropionyl]phenothiazin-2-yl¿ carbamate, possess the structural characteristics thought to be necessary for class 1 antiarrhythmic activity.


Subject(s)
Anti-Arrhythmia Agents/metabolism , Moricizine/metabolism , Prodrugs/metabolism , Adult , Anti-Arrhythmia Agents/administration & dosage , Female , Humans , Male , Molecular Structure , Moricizine/administration & dosage , Prodrugs/administration & dosage
14.
J Clin Pharmacol ; 36(12): 1161-8, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9013374

ABSTRACT

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.


Subject(s)
Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/pharmacokinetics , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/pharmacokinetics , Diltiazem/pharmacology , Diltiazem/pharmacokinetics , Moricizine/pharmacology , Moricizine/pharmacokinetics , Adolescent , Adult , Anti-Arrhythmia Agents/adverse effects , Area Under Curve , Biotransformation , Blood Proteins/metabolism , Calcium Channel Blockers/adverse effects , Chromatography, High Pressure Liquid , Diltiazem/adverse effects , Drug Interactions , Half-Life , Humans , Male , Moricizine/adverse effects , Protein Binding
15.
J Pharm Biomed Anal ; 14(12): 1717-25, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8887719

ABSTRACT

A sensitive and specific high-performance liquid chromatographic method with electrochemical detection was developed for the simultaneous determination of naltrexone and its major metabolite, 6-beta-naltrexol, in human plasma. After alkalinizing 2 ml plasma samples with pH 9 sodium carbonate buffer, naltrexone and 6-beta-naltrexol were extracted into dichloromethane and then back-extracted into 0.017 M phosphoric acid. A portion of the acid extract was chromatographed on a YMC phenyl column using a mobile phase of methanol-phosphoric acid (50 mM) (20:80, v/v) (pH* 3.2) at a flow-rate of 1.2 ml min 1. Quantification was performed using an ESA Coulometric electrochemical detector. Acceptable intra-day and assay precision (RSD < 10%) and accuracy (< 16%) for both compounds were observed over concentration ranges of 0.25-50.0 ng ml-1 for naltrexone and 0.5-100 ng ml-1 for 6-beta-naltrexol. No degradation of either naltrexone or 6-beta-naltrexol was observed in frozen human plasma stored at -20 degrees C over an 8 month period. The method is sufficiently sensitive and selective to quantify plasma concentrations of naltrexone and 6-beta-naltrexol after oral doses of 50 mg of naltrexone to healthy subjects or alcoholic patients.


Subject(s)
Naltrexone/analogs & derivatives , Naltrexone/blood , Narcotic Antagonists/blood , Chromatography, Liquid/methods , Electrochemistry/methods , Humans , Reproducibility of Results , Sensitivity and Specificity
16.
Pharm Res ; 12(12): 1874-7, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8786959

ABSTRACT

PURPOSE: To examine the pharmacokinetics of warfarin after administration of single oral doses (2, 5, and 10 mg) to healthy male volunteers. METHODS: A sensitive reverse-phase HPLC method was used to quantify warfarin plasma concentrations as low as 6 ng/ml. Blood samples were collected for up to 120 hours following administration of these doses. RESULTS: As the dose decreased from 5 to 2 mg, the apparent volume of distribution (V/F) increased from 12 to 21 liters and the terminal half-life (t1/2) increased from 47 to 71 hours. Oral clearance remained unchanged over the examined dose range. These apparent dose-dependent changes in warfarin's t1/2 and V/F may be due to saturable tissue binding of this drug. It appears that a previously undetected and prolonged terminal phase may exist but can not be adequately characterized with the 120-hour sampling interval. To evaluate this long t1/2, a follow-up study was conducted to examine warfarin's pharmacokinetics for up to 21 days following a 10-mg dose. The prolonged terminal phase started to become apparent when plasma levels declined to less than 100 ng/ml. The t1/2 of this terminal phase was determined to be approximately one week. CONCLUSIONS: This is the first report that documents the dose-dependent pharmacokinetics of warfarin and the previously unreported long t1/2 of one week for warfarin in humans.


Subject(s)
Warfarin/pharmacokinetics , Administration, Oral , Adult , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Humans , Male
17.
J Clin Pharmacol ; 35(12): 1181-6, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8750369

ABSTRACT

Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin (acetylsalicylic acid; ASA) are limited. This single-center study was designed to determine the rate and extent of oral absorption of 80-mg ASA tablets in healthy, young male subjects and to assess the intra- and inter-subject variability of ASA pharmacokinetics and platelet aggregation effects. Ten subjects each received a single, open-label, oral 80-mg ASA dose on three separate days. Each dose was separated by a 2-week washout interval. Blood samples for pharmacokinetic determinations of ASA and its metabolite, salicylic acid (SA) and platelet aggregation studies were obtained at scheduled timepoints before and up to 24 hours after each dose. Peak plasma ASA levels of 1 microgram/mL were achieved within 30 minutes. Peak plasma SA levels of approximately 4 micrograms/mL were attained in 1 hour. The terminal half-lives (t1/2) of ASA and SA were 0.4 and 2.1 hours, respectively. Both ASA and SA pharmacokinetics and the platelet aggregation response to ASA exhibited considerable intra- and inter-subject variability. Inhibition of platelet aggregation was found to relate with ASA area under the plasma concentration versus time curve (AUC).


Subject(s)
Aspirin/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Adult , Aspirin/administration & dosage , Aspirin/pharmacology , Humans , Male , Platelet Aggregation/drug effects , Salicylates/pharmacokinetics , Salicylic Acid
18.
J Clin Pharmacol ; 35(1): 22-30, 1995 Jan.
Article in English | MEDLINE | ID: mdl-7751410

ABSTRACT

The pharmacokinetics, safety, and tolerance of linopiridine ([3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one]; DuP 996) a potential therapeutic agent for Alzheimer's disease, were assessed in double-blind, placebo-controlled, randomized studies in which single oral doses were given to 64 healthy young or elderly males. Young subjects received escalating doses of 0.5 to 55 mg, whereas elderly subjects were given doses of 20 to 45 mg. Linopirdine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection. In both groups, linopirdine disposition was characterized by rapid absorption (mean Tmax, < 1 hr) and elimination (mean t1/2, 0.4-3.2 hr). Urinary excretion of unchanged drug was negligible. The pharmacokinetic parameters showed large inter- and intrasubject variability. Linopirdine was well-tolerated in both young and elderly volunteers. The most frequently reported adverse event was headache. The subjects who received linopirdine did not experience clinically important changes in vital signs, electrocardiograms (ECGs), electroencephalograms (EEGs), or clinical laboratory evaluations.


Subject(s)
Indoles/pharmacokinetics , Pyridines/pharmacokinetics , Administration, Oral , Adolescent , Adult , Aged , Double-Blind Method , Drug Administration Schedule , Drug Tolerance , Humans , Indoles/blood , Indoles/pharmacology , Indoles/urine , Male , Pyridines/blood , Pyridines/pharmacology , Pyridines/urine , Tablets
19.
J Pharm Biomed Anal ; 12(9): 1163-72, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7803568

ABSTRACT

A sensitive and specific high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for the simultaneous determination of DuP 128 (N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)p entyl]-N- hepthylurea), an ACAT inhibitor, its sulphone metabolite (XB277), and the separate determination of sulphoxide metabolite (XC164) in human plasma. After deproteinizing plasma samples with acetonitrile, the organic layer, created by adding approximately 0.25 g of NaCl, was removed, evaporated to dryness, and the residue then reconstituted with 400 microliters of acetonitrile. The acetonitrile layer was washed with 5 ml of hexane and then 50 microliters was injected into the HPLC. DuP 128 and XB277 were simultaneously quantified using a YMC basic column and fluorescence detection (lambda Ex = 270 nm and lambda Em = 385 nm). XC164 was quantified using a Waters microBondpack C18 reversed-phase column and fluorescence detection (lambda Ex = 270 nm and lambda Em = 365 nm). The relationship between the peak height and plasma concentrations best fit a power curve and showed an average correlation coefficient of > 0.99 over a concentration range of 1-200 ng ml-1 for DuP 128 and XC164 and 2.5-200 ng ml-1 for XB277. Good intraday and interday assay precisions (RSD < 10%) and accuracy (< 14%) for all three compounds were observed. The methods were sufficiently sensitive and selective to quantify plasma concentrations of DuP 128 and its sulphoxide and sulphone metabolites after oral administration of single or multiple dose(s) of > 350 mg of DuP 128 to healthy subjects.


Subject(s)
Anticholesteremic Agents/blood , Imidazoles/blood , Sterol O-Acyltransferase/antagonists & inhibitors , Urea/analogs & derivatives , Administration, Oral , Chromatography, High Pressure Liquid/methods , Fluorescence , Humans , Male , Sulfones/blood , Sulfoxides/blood , Urea/blood
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