Omkar Prasad Asthana

High performance liquid chromatographic (HPLC) determination of centchroman in human serum and application to single-dose pharmacokinetics

A simple and sensitive (2 ng/ml) HPLC method with fluorescence detection has been developed to measure serum concentrations of centchroman, a new nonsteroidal antifertility agent. The method was sufficiently sensitive to follow the drug over 21 days in human volunteers. Pharmacokinetic parameters of centchroman were determined after a single oral dose of 60 mg (2 × 30-mg tablets) in two healthy female volunteers. Centchroman is slowly eliminated from serum, showing a biexponential disappearance curve from serum. The terminal half-life of centchroman in the two volunteers was 168 and 175 hr, respectively.

Pharmacokinetics of centchroman in healthy female subjects after oral administration

The pharmacokinetics of centchroman, a non-steroidal antifertility agent, were assessed in serum of eleven healthy female subjects after a single 30 mg oral dose. Maximum serum concentration (Cmax) of 55.53 (s.d., 15.45) microgram/L was attained at 5.18 (s.d., 1.78) h after oral administration. The concentration-time profile was best described by a two-compartment open model with bi-exponential disposition functions. The mean terminal elimination half-life (t1/2) was 165 (s.d., 49) h with a clearance of 6.17 (s.d., 1.67) L/h and volume of distribution of 1420 (s.d., 478) L. Comparison of the pharmacokinetic parameters of this study with those obtained after a single 60 mg oral dose did not show statistically significant differences in the rate of absorption, distribution and elimination. The Cmax and AUC0-infinity were dose-dependent. Thus, the absorption and disposition of centchroman are of first-order, reproducible and dose-dependent.

Optimization of contraceptive dosage regimen of Centchroman.

Centchroman (Ormeloxifene), a non-steroidal oral contraceptive, is used at a dose of 30 mg once a week. To prevent failures in the beginning of the therapy, it is recommended that a dose of 30 mg twice a week for 12 weeks be administered to build up adequate blood levels. The present study was undertaken to simplify the dosing schedule without sacrificing the purpose of twice a week dosing regimen, using modeling and measurement approaches. The drug was given to 60 female volunteers who were divided into seven groups: group I, 30 mg weekly; group II, 30 mg twice a week; group III, 30 mg twice a week for 12 weeks followed by 30 mg weekly; group IV, 30 mg twice a week for 6 weeks followed by 30 mg weekly; group V, 60 mg weekly; and groups VI and VII, single 60 mg loading dose followed by 30 mg weekly doses. The blood samples were collected and analyzed by HPLC. In group I, mean trough concentrations of centchroman and its active metabolite, 7-desmethyl centchroman, were comparable to the steady-state trough concentrations in groups III, IV, VI, and VII. The metabolite to parent drug ratio remained constant in all the groups. The pharmacokinetic parameters in group VII were comparable to those reported after a single 30 mg dose. Dosage regimen VI was more convenient and provided better pregnancy protection (Pearl index 1.18; unpublished report) than regimen III, which is currently on the market and, thus, could be effectively used for contraception.

Clinical Pharmacokinetics of the Diastereomers of Arteether in Healthy Volunteers

ObjectiveTo evaluate the pharmacokinetics of α- and β-diastereomers of arteether in healthy male volunteers.Participants and methodsThe study was a single-centre clinical pharmacokinetic trial in healthy male subjects. A group comprising 13 subjects aged 25–50 years received a single intramuscular 150mg individual dose of the arteether formulation containing α- and β-isomers in a 30: 70 ratio. Serial blood samples collected over a period of 0–192 hours were analysed by high-performance liquid chromatography-electrospray ionisation/tandem mass spectrometry and the plasma concentrations were subjected to compartmental and noncompartmental analyses. Pharmacodynamic parameters such as area under the inhibitory curve, ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC), maximum plasma concentration to MIC (Cmax/MIC) and time that plasma concentration exceeds the MIC (T>MIC) were calculated in vitro in four strains of Plasmodium falciparum to evaluate the in vivo effectiveness of the proposed dosage regimen.ResultsThere were no adverse effects observed during the study. The extent of metabolism of arteether to dihydroartemisinin (DHA) was low (∼5%) so as to be therapeutically nonsignificant. The pharmacokinetic profiles of the arteether diastereomers were different, and the maximum plasma concentrations of α- and β-isomers were reached at 4.77 ± 1.21 hours and 6.96 ± 1.62 hours, respectively, after which they showed biphasic decline with apparent terminal elimination half-lives of 13.24 ± 1.08 hours and 30.17 ± 2.44 hours, respectively. The plasma and renal clearances, as well as whole blood to plasma partition ratios of the isomers, were comparable, while the apparent volume of distribution during terminal phase of the β-isomer was approximately 3-fold higher than that of the α-isomer. In vitro erythrocyte culture experiments with four strains of P. falciparum showed similar MICs for both isomers of arteether. The highest observed MIC of 8 µg/L was selected for estimating the pharmacokinetic and pharmacodynamic parameters, which showed excellent correlation with published data on the clinical efficacy of arteether.ConclusionThe pharmacokinetics of arteether isomers demonstrated stereoselectivity, which was reflected mainly in the volume of distribution and the terminal elimination half-life. The α- and β-isomers of arteether appeared to compliment each other pharmacokinetically, with the α-isomer providing comparatively rapid and higher plasma concentrations resulting in immediate reduction in percentage parasitaemia, while the β-isomer, with its longer terminal elimination half-life, mean residence time and sustained plasma concentrations, maintained the activity for longer periods. The extent of metabolic conversion of arteether to DHA was minimal, so as to have any therapeutic or toxic significance.

Centchroman: A new non-steroidal oral contraceptive in human milk

Centchroman, a non-steroidal oral contraceptive drug, was given to 13 nursing mothers comprising two groups. Each participant in group I (n = 8) received a single 30 mg dose, and in group II (n = 5) each participant received a 30 mg twice a week dose for twelve weeks. Simultaneous blood and milk samples were collected and analyzed for the parent drug by high performance liquid chromatography. In the single dose study (group I), the mean +/- peak centchroman concentrations in milk and serum were 78.7 +/- 28.4 and 63.6 +/- 23.6 ng/ml with milk-to-serum (M/S) ratio of 1.4 +/- 0.9. There was no significant increase in centchroman concentrations in milk after multiple dosing (group II). However, serum concentrations reached up to 112.5 ng/ml at 6 h after the 13th dose. Average M/S ratios were insignificantly different at trough (prior to next dose) and at peak (4-6 h after dose) centchroman levels. Additionally, the breast milk and serum centchroman concentrations showed a significant correlation (r = 0.64, P < 0.01), indicating that the amount of centchroman excreted into breast milk is dependent on serum concentrations. The weekly dose (% of the maternal dose) of centchroman ingested by the breast-fed infant at peak maternal serum and milk levels was in the range of 0.4 to 11.5%, assuming a weekly milk uptake of 1.05 l/kg. There was no significant difference in the dose ingested by the infants between the two dosing groups. These levels of centchroman passing into breast milk and subsequent exposure to the infants are unlikely to be of any physiological consequence.

Pharmacokinetics of Centchroman in Nursing Women and Passage into Breast Milk

SummaryThe pharmacokinetics of centchroman (ormeloxifene), a nonsteroidal antifertility agent, was determined in 4 nursing mothers in the postpartum period after a single 30mg oral dose of the drug. The concentration-time profile of centchroman in serum and milk were not parallel. The milk/serum (M/S) area under the curve ratio of centchroman was 1.47 ± 0.56. Individual mean M/S concentration ratios of centchroman showed significant interindividual variation (range 0.38 to 1.94). A comparison of pharmacokinetic parameters in the nursing women with those reported previously in nonlactating women showed an insignificant difference; time to maximum concentration occurred later in milk than in maternal serum. The average infant dose of centchroman via breast milk, assuming a weekly milk intake of 1.05 L/kg and 100% absorption, would be 7.43 ± 3.18% per week of the maternal dose.

Simultaneous determination of centbutindole and its hydroxy metabolite in serum by high-performance liquid chromatography☆

A high-performance liquid chromatographic assay has been developed and validated for the determination of centbutindole and its hydroxy metabolite in serum. The method involves extraction of serum samples with diethyl ether at pH greater than 8, back-extraction into 0.5 M hydrochloric acid and finally again with diethyl ether after addition of 2 M potassium hydroxide. Separation was accomplished by reversed-phase high-performance liquid chromatography on a cyano column with an acetonitrile-phosphate buffer system. The recovery of centbutindole and its metabolite was always greater than 80%. Calibration curves were linear over the concentration range 0.25-5 ng/ml for centbutindole and 0.05-1 ng/ml for the hydroxy metabolite. Although the lower limit of detection was 0.1 ng/ml for centbuntindole and 0.02 ng/ml for the hydroxy metabolite, the reliable limits of quantitation were 0.25 and 0.05 ng/ml, respectively, using 4 ml of serum.

PRE-CLINICAL AND CLINICAL PHARMACOKINETICS OF THE DIASTEREOMERS OF ARTEETHER, A POTENT ANTIMALARIAL

The pharmacokinetics of α- and β-diastereomers of Arteether, a well-known antimalarial drug and its active metabolite dihydroartemisinin (DHA) were studied in Sprague-Dawley rats, Rhesus monkeys and human volunteers. The ratio of α- and β-isomers was maintained at 30: 70 in the formulations used for the study. Pre-clinical studies were carried out (N=3) by oral, intramuscular and intravenous routes, while clinical studies (N=13) were performed intramuscularly. Studies in rats revealed dose dependency/ non-linearity in arteether pharmacokinetics with in the dose levels used. Overall the pharmacokinetic properties of both isomers were similar in rats, monkeys and humans, with β-isomer exhibiting longer elimination half-life, MRT, volume of distribution and clearance, irrespective of the route of administration. But there appeared to be species difference in arteether metabolism, highest conversion being recorded with humans followed by rats and monkeys. The α-isomer exhibited rapid and significantly higher peak plasma concentrations in all the species post intramuscular administrations, while β-isomer showed prolonged plasma levels. This suggests that the rapid initial reduction in percent parasitemia may be due to α- isomer and the activity is maintained by the β- isomer. Because of their complimentary pharmacokinetic characteristics, the isomeric mixture of arteether can be therapeutically more beneficial than β- isomer used alone.

Single Oral Dose Pharmacokinetics of Centbutindole, a New Neuroleptic Agent, in Healthy Human Volunteers

SummaryCentbutindole, a butyrophenone derivative, is a new neuroleptic agent developed at the Central Drug Research Institute, Lucknow, India. The pharmacokinetics of this compound were investigated after oral administration of single 3mg tablets in 5 healthy male volunteers. Serum levels of the unchanged drug were measured by high pressure liquid chromatography (HPLC) with fluorescence detection. Mean peak serum levels (3.48 ± 1.58 mg/L) were reached at 4 hours, and the mean biological half-life was calculated as 12.45 ± 3.59 hours. The data were best fitted to a 1-compartment open model with first-order absorption and elimination kinetics. Considerable intersubject variability was noted in the absorption characteristics of centbutindole, and further study is planned to better define the pharmacokinetics of this drug.

Preliminary pharmacokinetics of a new anthelmintic agent, CDRI-81/470 in healthy subjects

Abstract Single dose pharmacokinetic study of CDRI-81/470, a new broad spectrum anthelmintic agent, was carried out in 12 healthy human subjects after a single 375-mg oral dose. The serum, saliva and urine samples were analyzed by HPLC. The compound attained peak serum levels of 15.1±4.6 μg/ml in 2.6±1.1 h and could be measured up to 5 days. Mean serum AUC was 195±69 μg per h/ml. The compound showed a mean apparent elimination half-life of 12.1±4.5 h while mean residence time (MRT) was found to be 11.1±1.7 h. Extent of urinary excretion of CDRI-81/470 (2.3±0.7%) was less than that of its decarboxylate metabolite (5.3±2.2%) up to 10 h post dose. In vivo protein binding in serum was 93.1±1.2% and remained constant over in vivo concentration range. The salivary levels of CDRI-81/470 were higher than the corresponding unbound serum levels. There was a significant correlation between serum and salivary levels of CDRI-81/470, with a mean ratio of saliva to unbound serum levels of 2.04±0.24, indicating the possibility of predicting serum concentrations of CDRI-81/470 from non-invasive salivary sampling technique.