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Determination of a new antimalarial drug, benflumetol, in blood plasma by high-performance liquid chromatography

Mansor SM, Navaratnam V, Yahaya N, Nair NK, Wernsdorfer WH, Degen PH

J Chromatogr B Biomed Appl, 1996 Jul 12;682(2):321-5.
PMID: 8844426

A rapid and selective high-performance liquid chromatographic assay for determination of a new antimalarial drug (benflumetol, BFL) is described. After extraction with hexane-diethyl ether (70:30, v/v) from plasma, BFL was analysed using a C18 Partisil 10 ODS-3 reversed-phase stainless steel column and a mobile phase of acetonitrile-0.1 M ammonium acetate (90:10, v/v) adjusted to pH 4.9 with ultraviolet detection at 335 nm. The mean recovery of BFL over a concentration range of 50-400 ng/ml was 96.8 +/- 5.2%. The within-day and day-to-day coefficients of variation were 1.8-4.0 and 1.8-4.2%, respectively. The minimum detectable concentration in plasma for BFL was 5 ng/ml with a C.V. of less than 10%. This method was found to be suitable for clinical pharmacokinetic studies.

Matched MeSH terms: Area Under Curve
Bioavailability and pharmacokinetics of acyclovir tablet preparation

Yuen KH, Peh KK, Billa N, Chan KL, Toh WT

Drug Dev Ind Pharm, 1998 Feb;24(2):193-6.
PMID: 15605452

The bioavailability of a generic preparation of acyclovir (Avorax) was compared with the innovator product, Zovirax. Twelve healthy volunteers participated in the study, conducted according to a randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration time curve (AUC(0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the Tmax or the logarithmic transformed AUC(0-infinity) and C(max) values of the two preparations. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC(0-infinity) values of Avorax over those of Zovirax was found to lie between 0.85 and 1.06, while that of the logarithmic transformed Cmax values was between 0.95 and 1.25, being within the bioequivalence limit of 0.80-1.25. Moreover, the elimination rate constant (k(e)), elimination half-life (t(1/2)), and apparent volume of distribution (Vd) values obtained with the two preparations were comparable and not significantly different statistically.

Matched MeSH terms: Area Under Curve
Comparative bioavailability study of two atenolol tablet preparations

Peh KK, Yuen KH, Wong JW, Toh WT

Drug Dev Ind Pharm, 1999 Mar;25(3):357-60.
PMID: 10071830

A study was conducted to compare the bioavailability of a generic product of atenolol (Normaten FC) with the innovator product, Tenormin. Twelve healthy adult volunteers participated in the study conducted according to a randomized, two-way crossover design. The preparations were compared using area under the plasma concentration-time curve AUC0-infinity, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was obtained between the Tmax values and the logarithmic transformed AUC0-infinity and Cmax values of the two products. Moreover, the 90% confidence interval for the ratio of the logarithmically transformed AUC0-infinity values of Normaten FC over those of Tenormin was found to lie between 0.82 and 0.98, while that of the logarithmically transformed Cmax values was between 0.82 and 1.09, both being within the bioequivalence limit of 0.80-1.25. The values of elimination half-life t1/2 between the two products were also found comparable and not significantly different statistically. The t1/2 values obtained in our study were slightly longer than those reported in the literature for other population groups.

Matched MeSH terms: Area Under Curve
Comparative bioavailability study of a generic naltrexone tablet preparation

Yuen KH, Peh KK, Billa N

Drug Dev Ind Pharm, 1999 Mar;25(3):353-6.
PMID: 10071829

The bioavailability of a generic preparation of naltrexone (Narpan) was compared with the innovator product, Trexan. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration-time curve AUC0-infinity, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was observed between the logarithmic transformed AUC0-infinity and the logarithmically transformed Cmax values of the two preparations. Also, no statistically significant difference was observed between the untransformed Tmax values. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity values of Narpan over those of Trexan was found to lie between 0.87 and 1.01, while that of the logarithmic transformed Cmax values was between 0.94 and 1.23, both being within the bioequivalence limit of 0.80-1.25. The numerical values of the elimination half-life (t1/2) obtained with the two preparations were also not significantly different and were comparable to those reported in the literature.

Matched MeSH terms: Area Under Curve
Bioequivalence of a generic metformin tablet preparation

Yuen KH, Wong JW, Billa N, Julianto T, Toh WT

Int J Clin Pharmacol Ther, 1999 Jul;37(7):319-22.
PMID: 10442505

The bioavailability of a generic preparation of metformin (Diabetmin from Hovid Sdn Bhd) was evaluated in comparison with a proprietary product (Glucophage from Lipha Pharma Ltd., UK).

Matched MeSH terms: Area Under Curve
Improved bioavailability of vitamin E with a self emulsifying formulation

Julianto T, Yuen KH, Noor AM

Int J Pharm, 2000 Apr 25;200(1):53-7.
PMID: 10845685

A single dose study was conducted to evaluate the bioavailability of a novel self-emulsifying vitamin E preparation, in comparison with that of a commercial product, Natopherol, available as soft gelatin capsules under fasted condition. The self-emulsifying preparation achieved a faster rate and higher extent of absorption. A statistically significant difference was observed between the values of the two preparations in the parameters AUC, Cmax and Tmax. Moreover, the 90% confidence interval of the logarithmic transformed AUC values of the self-emulsifying preparation over those of the soft gelatin capsule product was found to be between 2.1 and 4.1, suggesting an increase in bioavailability of between 210 and 410%. As for Cmax, the 90% confidence interval was between 2.1 and 3.0. However, no statistically significant difference was observed between the t(1/2) values estimated from the plasma concentration versus time data of the two preparations. The values are also comparable to those reported in the literature.

Matched MeSH terms: Area Under Curve
Gamma-scintigraphic study of the gastrointestinal transit and in vivo dissolution of a controlled release diclofenac sodium formulation in xanthan gum matrices

Billa N, Yuen KH, Khader MA, Omar A

Int J Pharm, 2000 May 15;201(1):109-20.
PMID: 10867269

A xanthan gum matrix controlled release tablet formulation containing diclofenac sodium was evaluated in vitro and was found to release the drug at a uniform rate. The gastrointestinal transit behaviour of the formulation as determined by gamma scintigraphy, using healthy male volunteers under fasted and fed conditions, indicated that gastric emptying was delayed with food intake. In contrast, the small intestinal transit remained practically unchanged under both food statuses. Therefore, the delay in caecal arrival observed in the fed state can be attributed to the delay in gastric emptying. Rate of diclofenac sodium absorption was generally higher in the fed state compared to the fasted state, however the total amount absorbed under both food statuses remained practically the same. The rate of in vivo dissolution of the drug in the fed state was faster compared to that in the fasted state. Thus, at the time of caecal arrival, in vivo dissolution was complete in the fed state, unlike in the fasted state, where almost 60% of the drug was delivered to the colon.

Matched MeSH terms: Area Under Curve
Quantification of (+)-calanolide A, a novel and naturally occurring anti-HIV agent, by high-performance liquid chromatography in plasma from rat, dog and human

Xu ZQ, Norris KJ, Weinberg DS, Kardatzke J, Wertz P, Frank P, et al.

J Chromatogr B Biomed Sci Appl, 2000 Jun 09;742(2):267-75.
PMID: 10901131

A HPLC method was validated for quantification of (+)-calanolide A (1), a novel anti-HIV agent, in rat, dog and human plasma. The synthetic intermediate (+/-)-12-oxocalanolide A (2) was found to be a suitable internal standard. Compounds were extracted from plasma using a solid-phase C(18) cartridge and quantified over the assay range of 12.5 to 800 ng/ml. The method was utilized to determine (+)-calanolide A pharmacokinetics in rats, dogs and humans. This is the first report of a validated HPLC assay for determination of (+)-calanolide A concentrations in rat and dog plasma as well as human plasma obtained from clinical trials. There was no evidence of in vivo epimerization of (+)-calanolide A to its inactive epimer (+)-calanolide B (3).

Matched MeSH terms: Area Under Curve
Comparative bioavailability study of two controlled-release pentoxifylline tablet preparations

Yuen KH, Wong JW, Peh KK, Julianto T, Choy WP

Drug Dev Ind Pharm, 2000 Jul;26(7):803-7.
PMID: 10872103

The bioavailability of a generic preparation of pentoxifylline sustained-release (SR) tablet was evaluated in comparison with a proprietary product (Trental 400). For the study, 12 healthy male volunteers participated; the study was conducted according to a randomized, two-way crossover design. The bioavailability was compared using the parameters total area under the plasma level-time curve AUC0-infinity, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was observed between the values of the two products in all three parameters. The 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity values of the generic pentoxifylline over those of Trental 400 was found to lie between 0.83 and 1.00, while that of the parameter Cmax was between 0.91 and 1.29. In addition, elimination half-life t1/2 and apparent volume of distribution Vd were calculated. There was no statistically significant difference between the t1/2 Vd values obtained from the data of the two preparations.

Matched MeSH terms: Area Under Curve
Estimated coefficient of variation values for sample size planning in bioequivalence studies

Yuen KH, Wong JW, Yap SP, Billa N

Int J Clin Pharmacol Ther, 2001 Jan;39(1):37-40.
PMID: 11204936

OBJECTIVE: The aim of the present communication is to provide information regarding the intrasubject coefficent of variation obtained from 30 bioequivalence studies covering 16 drugs which can be used for estimation of sample size. Additionally, an attempt was also made to estimate the test power of each of the studies conducted.
METHODS: The intrasubject coefficient of variation was estimated from the residual mean square error obtained from analysis of variance of the parameters AUC0-infinity, Cmax and Cmax/AUC0-infinity after logarithmic transformation. The test power in the analyses of the above parameters was subsequently estimated using nomograms provided by Diletti et al. [1991].
RESULTS AND CONCLUSION: Thirty products covering 16 drugs were studied in which 22 were immediate-release (including one dispersible tablet) and 8 were sustained-release formulations. The intrasubject coefficient of variation for the parameter AUC0-infinity was smaller than Cmax, and hence considerably more studies were able to attain a power of greater than 80% using 12 volunteers for the AUC0-infinity, compared to the Cmax. However, the variability in the Cmax could be reduced by using the parameter Cmax/ AUC0-infinity, and thus, provide a more realistic estimation of sample size, since the latter reflects only the rate of absorption and not both the rate and extent as in the case of Cmax [Endrenyi et al. 1991].

Matched MeSH terms: Area Under Curve
Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status

Yap SP, Yuen KH, Wong JW

J Pharm Pharmacol, 2001 Jan;53(1):67-71.
PMID: 11206194

We have investigated the pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under fed and fasted conditions in eight healthy volunteers. The volunteers were administered a single oral dose of mixed tocotrienols (300 mg) under fed or fasted conditions. The bioavailability of tocotrienols under the two conditions was compared using the parameters peak plasma concentration (Cmax), time to reach peak plasma concentration (Tmax) and total area under the plasma concentration-time curve (AUC(o-infinity)). A statistically significant difference was observed between the fed and fasted logarithmic transformed values of Cmax (P < 0.01) and AUC(0-infinity) (P < 0.01) for all three tocotrienols. In addition, the 90% confidence intervals for the ratio of the logarithmic transformed AUC(0-infinity) values of alpha-, gamma- and delta-tocotrienols under the fed state over those of the fasted state were found to lie between 2.24-3.40, 2.05-4.09 and 1.59-3.81, respectively, while those of the Cmax were between 2.28-4.39, 2.31-5.87 and 1.52-4.05, respectively. However, no statistically significant difference was observed between the fed and fasted Tmax values of the three homologues. The mean apparent elimination half-life (t(1/2)) of alpha-, gamma- and delta-tocotrienols was estimated to be 4.4, 4.3 and 2.3 h, respectively, being between 4.5- to 8.7-fold shorter than that reported for alpha-tocopherol. No statistically significant difference was observed between the fed and fasted t(1/2) values. The mean apparent volume of distribution (Vd/f) values under the fed state were significantly smaller than those of the fasted state, which could be attributed to increased absorption of the tocotrienols in the fed state.

Matched MeSH terms: Area Under Curve
Improved oral bioavailability of artemisinin through inclusion complexation with beta- and gamma-cyclodextrins

Wong JW, Yuen KH

Int J Pharm, 2001 Oct 04;227(1-2):177-85.
PMID: 11564552

The bioavailability of beta- and gamma-cyclodextrin artemisinin complexes was evaluated in comparison with a normal commercially available preparation, Artemisinin 250. Twelve healthy male volunteers participated in the study conducted according to a three-way crossover design. The bioavailability was compared using the parameters, total area under the plasma level-time curve (AUC(0-infinity)), peak plasma concentration (C(max)), and time to reach peak plasma concentration (T(max)). A statistically significant difference was observed between the values of the complexes and Artemisinin 250 for the three parameters. However, no statistically significant difference was observed between the values of the beta- and gamma-cyclodextrin complexes. Moreover, the 90% confidence interval for the ratio of the AUC(0-infinity) values of the beta-cyclodextrin complex over those of Artemisinin 250 was estimated to be between 1.51-2.04, while that of C(max) was between 1.73-2.93. For the gamma-cyclodextrin complex, the respective intervals were 1.30-1.76 and 1.43-2.43. These findings indicated that the beta- and gamma-cyclodextrin complexes had a much higher rate and extent of bioavailability compared to Artemisinin 250. In addition, the absorption of artemisinin was observed to be poor and negligible when the preparations started to arrive in the colon. This could be attributed to poor dissolution of artemisinin in the semi-solid faecal matter in the lower part of the gastrointestinal tract.

Matched MeSH terms: Area Under Curve
Fulltext Comparative bioavailability study of a generic sustained release diclofenac sodium tablet

Magosso E, Yuen KH, Choy WP, Ling SSN, Ng BH, Ur-Rahman N, et al.

Med J Malaysia, 2004 Aug;59(3):352-6.
PMID: 15727381

The bioavailability of a generic diclofenac sodium sustained release tablet preparation (Zolterol, SR) was compared with the innovator product, Voltaren, SR. Twelve healthy adult male volunteers participated in the study, which was conducted according to a randomized, two-way crossover design with a wash out period of one week. The bioavailability of diclofenac was compared using the parameters area under the plasma concentration-time curve (AUC(0-infinity)), peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed for both logarithmically transformed AUC(0-infinity), Cmax values and Tmax value of the two preparations.

Matched MeSH terms: Area Under Curve
Influence of lipolysis and droplet size on tocotrienol absorption from self-emulsifying formulations

Yap SP, Yuen KH

Int J Pharm, 2004 Aug 20;281(1-2):67-78.
PMID: 15288344

A single dose comparative bioavailability study was conducted to evaluate the bioavailability of tocotrienols from two self-emulsifying formulations, one of which produced an emulsion that readily lipolysed under in vitro condition (SES-A), while the other produced a finer dispersion with negligible lipolysis (SES-B) in comparison with that of a non-self-emulsifying formulation in soya oil. The study was conducted according to a three-way crossover design using six healthy human volunteers. Statistically significant differences were observed between the logarithmic transformed peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC(0-infinity)) values of both SES-A and -B compared to NSES-C indicating that SES-A and -B achieved a higher extent of absorption compared to NSES-C. Moreover, the 90% confidence interval of the AUC(0-infinity) values of both SES-A and -B over those of NSES-C were between 2-3 suggesting an increase in bioavailability of about two-three times compared to NSES-C. Both SES-A and -B also achieved a faster onset of absorption. However, both SES-A and -B had comparable bioavailability, despite the fact that SES-B was able to form emulsions with smaller droplet size. Thus, it appeared that both droplet sizes as well as the rate and extent of lipolysis of the emulsion products formed were important for enhancing the bioavailability of the tocotrienols from the self-emulsifying systems.

Matched MeSH terms: Area Under Curve
Significance of lipid matrix aging on in vitro release and in vivo bioavailability

Choy YW, Khan N, Yuen KH

Int J Pharm, 2005 Aug 11;299(1-2):55-64.
PMID: 15955645

A polyglycolised glyceride carrier, Gelucire 50/13, was incorporated with paracetamol as a model drug, filled into hard gelatin capsules and stored at three different temperatures for various lengths of time. The resultant solidified matrix within the capsule was subjected to thermal analysis using differential scanning calorimetry (DSC) to ascertain its supramolecular structure. Polymorphic transformations towards more stable gelucire forms were observed upon aging the matrices, with samples stored at a temperature near the melting range of the lower temperature gelucire melting fraction showing the most profound changes. The increase in the rate of drug release from aged samples could be correlated to the alterations to the supramolecular structure of the gelucire. Accelerated drug release from aged samples could also be seen from in vivo studies using healthy human volunteers, although the extent of absorption was not affected. Therefore, even though the sustainability of release may be compromised by aging the gelucire matrices, the bioavailability of the incorporated drug is unlikely to be affected.

Matched MeSH terms: Area Under Curve
Bioavailability and pharmacokinetic studies of eurycomanone from Eurycoma longifolia

Low BS, Ng BH, Choy WP, Yuen KH, Chan KL

Planta Med, 2005 Sep;71(9):803-7.
PMID: 16206032

A validated HPLC analysis of eurycomanone (1), a bioactive quassinoid, in rat plasma following oral and intravenous administration of Eurycoma longifolia Jack extract was developed for pharmacokinetic and bioavailability studies. Relatively high plasma eurycomanone concentrations were detected after an intravenous injection of 10 mg/kg extract F2 containing 1.96 mg/kg of the quassinoid. However, it declined rapidly to zero after 8 h. Its mean elimination rate constant (k(e)), biological half-life (t(1/2)), volume of distribution (V(d)) and clearance (CL) were 0.88 +/- 0.19 h (-1), 1.00 +/- 0.26 h, 0.68 +/- 0.30 L/kg and 0.39 +/- 0.08 L/h/kg, respectively. Following oral administration of eurycomanone, its Cmax and Tmax values were detected as 0.33 +/- 0.03 microg/mL and 4.40 +/- 0.98 h, respectively. The plasma concentration of the quassinoid after oral administration was much lower than after intravenous application in spite of the oral dose being 5 times higher. The results indicate that eurycomanone is poorly bioavailable when given orally. A comparison of the AUC (0-->infinity) obtained orally to that obtained after an intravenous administration (normalized for dose differences) revealed that the absolute bioavailability of the compound was low with 10.5 %. Furthermore, the compound appeared to be well distributed in the extravascular fluids because of its relatively high V(d) value. The poor oral bioavailability was not attributed to instability problems because eurycomanone has been shown to be stable under different pH conditions. Thus, its poor oral bioavailability may be due to poor membrane permeability in view of its low P value and/or high first-pass metabolism.

Matched MeSH terms: Area Under Curve
A new and simple solid-phase extraction method for LC determination of pyronaridine in human plasma

Ramanathan S, Karupiah S, Nair NK, Olliaro PL, Navaratnam V, Wernsdorfer WH, et al.

J Chromatogr B Analyt Technol Biomed Life Sci, 2005 Sep 25;824(1-2):45-50.
PMID: 16046285

A new approach using a simple solid-phase extraction technique has been developed for the determination of pyronaridine (PND), an antimalarial drug, in human plasma. After extraction with C18 solid-phase sorbent, PND was analyzed using a reverse phase chromatographic method with fluorescence detection (at lambda(ex)=267 nm and lambda(em)=443 nm). The mean extraction recovery for PND was 95.2%. The coefficient of variation for intra-assay precision, inter-assay precision and accuracy was less than 10%. The quantification limit with fluorescence detection was 0.010 microg/mL plasma. The method described herein has several advantages over other published methods since it is easy to perform and rapid. It also permits reducing both, solvent use and sample preparation time. The method has been used successfully to assay plasma samples from clinical pharmacokinetic studies.

Matched MeSH terms: Area Under Curve
Enhanced oral bioavailability and intestinal lymphatic transport of a hydrophilic drug using liposomes

Ling SS, Magosso E, Khan NA, Yuen KH, Barker SA

Drug Dev Ind Pharm, 2006 Mar;32(3):335-45.
PMID: 16556538

A liposome system was evaluated for oral delivery of a poorly bioavailable hydrophilic drug. The system was prepared from proliposome, which consisted of negatively charged phosphatidylcholine, whereas cefotaxime was chosen as the model drug. An in vivo study was carried out on nine rats according to a three-way crossover design to compare the oral bioavailability of cefotaxime from the liposomal formulation with that of an aqueous drug solution and a physical mixture of cefotaxime with blank liposomes. The results indicated that the extent of bioavailability of cefotaxime was increased approximately 2.7 and 2.3 times compared with that of the aqueous solution and the physical mixture, respectively. In a separate study, simultaneous determination of cefotaxime in intestinal lymph (collected from the mesenteric lymph duct) and in plasma (collected from the tail vein) revealed that its concentration was consistently higher in the lymph than in the plasma when administered via the liposomal formulation, whereas the reverse was observed with the aqueous solution. Thus, the results indicated that the liposomes system has the potential of increasing the oral bioavailability of poorly bioavailable hydrophilic drugs and also promote their lymphatic transport in the intestinal lymph.

Matched MeSH terms: Area Under Curve
Fulltext Categorization of low cardiorespiratory fitness using obesity indices in non-smoking Singaporean women

Pua YH, Lim CK, Ang A

Obesity (Silver Spring), 2006 Nov;14(11):1992-9.
PMID: 17135616 DOI: 10.1038/oby.2006.233

OBJECTIVE: To revisit cut-off values of BMI, waist circumference (WC), and waist-to-stature ratio (WSR) based on their association with cardiorespiratory fitness (CRF). The derived cut-off points were compared with current values (BMI, 25.0 kg/m(2); WC, 80 cm) as recommended by the World Health Organization.
RESEARCH METHODS AND PROCEDURES: Anthropometric indices were measured in a cross sectional study of 358 Singaporean female employees of a large tertiary hospital (63% Singaporean Chinese, 28% Malays, and 9% Indians). CRF was determined by the 1-mile walk test. Receiver operating characteristic curves were constructed to determine cut-off points.
RESULTS: The cut-off points for BMI, WC, and WSR were 23.6 kg/m(2), 75.3 cm, and 0.48, respectively. The areas under the curve of BMI, WC, and WSR were 0.68, 0.74, and 0.74, respectively. For a given BMI, women with low CRF had higher WSR compared with women with high CRF.
DISCUSSION: These findings provide convergent evidence that the cut-off points for Singaporean women were lower than the World Health Organization's criteria but were in good agreement with those reported for Asians.

Matched MeSH terms: Area Under Curve
Fulltext Bioequivalence evaluation of two different formulations of ciprofloxacin tablets in healthy volunteers

Hassan Y, Alfadly SO, Azmin MN, Peh KK, Tan TF, Noorizan AA, et al.

Singapore Med J, 2007 Sep;48(9):819-23.
PMID: 17728962

A bioequivalence study of two oral formulations of 500 mg tablets of ciprofloxacin (RAZA Pharmaniaga, Malaysia) as test and Ciprobay (Bayer AG, Germany) as reference, was carried out in 24 healthy human volunteers. Each volunteer received a single dose of ciprofloxacin.

Matched MeSH terms: Area Under Curve

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