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Fulltext Heavy Metal in Paddy Soil and its Bioavailability in Rice Using In Vitro Digestion Model for Health Risk Assessment

Zulkafflee NS, Mohd Redzuan NA, Hanafi Z, Selamat J, Ismail MR, Praveena SM, et al.

Int J Environ Res Public Health, 2019 11 28;16(23).
PMID: 31795132 DOI: 10.3390/ijerph16234769

Rice ingestion is one of the major pathways for heavy metal bioaccumulation in human. This study aimed to measure the heavy metal content of paddy soils and its bioavailability in paddy grain in order to assess the health risk. In total, 10 rice samples (50 g each) of paddy plants were harvested from the Selangor and Terengganu areas of Malaysia to assess the bioavailability of heavy metal (As, Cd, Cu, Cr, and Pb) using the in vitro digestion model of Rijksinstituut voor Volksgezondheid en Milieu. The bioavailability of heavy metal concentrations in rice samples were analyzed using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The findings showed the bioavailability of heavy metal concentrations was decreased in the order Cr > Cu > Pb > As > Cd. Chromium was found to be the most abundant bioavailable heavy metal in cooked rice, which was the result of its high content in paddy soil. Hazard Quotient values for the bioavailability of the heavy metal studied were less than one indicating no non-carcinogenic health risks for adults and children. Meanwhile, the total Lifetime Cancer Risk exceeded the acceptable value showing a potential of carcinogenic health risk for both adults and children. The application of in vitro digestion model in assessing bioavailability of heavy metal produces a more realistic estimation of human health risks exposure. However, a regular monitoring of pollution in Selangor and Terengganu areas is crucial since the exposure of heavy metals through rice consumption poses the potential non-carcinogenic and carcinogenic health risk to the local residents.

Matched MeSH terms: Biological Availability
Fulltext Comparative pharmacokinetics of a proliposome formulation of Ginkgo biloba extract and Ginaton in rats by a sensitive ultra performance liquid chromatography-tandem mass spectrometry method

Zheng B, Xing G, Bi Y, Yan G, Wang J, Cheng Y, et al.

Saudi J Biol Sci, 2016 Jan;23(1):54-65.
PMID: 26858539 DOI: 10.1016/j.sjbs.2015.08.009

As a novel oral drug delivery system, proliposome was applied to improve the solubility of active components of Ginkgo biloba extract (GbE). There are currently few reports focusing on the pharmacokinetic characteristics of proliposome of GbE (GbP). A rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of active components of GbP and a commercial tablet product (Ginaton) in rat plasma was developed and successfully validated. The method was applied to the comparative pharmacokinetic evaluation of GbP and Ginaton in rat plasma. The results indicated that GbP has a significant effect on absorption, elimination and bioavailability of flavonoids and terpenoid lactones in comparison with Ginaton. The obtained results would be helpful for evaluating the absorption mechanism in the gastrointestinal tract in pharmacokinetic level and guiding the development of the novel oral drug delivery system.

Matched MeSH terms: Biological Availability
Fulltext Insulin-Loaded Barium Salt Particles Facilitate Oral Delivery of Insulin in Diabetic Rats

Zaman R, Karim ME, Othman I, Zaini A, Chowdhury EH

Pharmaceutics, 2020 Jul 29;12(8).
PMID: 32751231 DOI: 10.3390/pharmaceutics12080710

Oral delivery is considered as the most preferred and yet most challenging mode of drug administration; especially a fragile and sensitive peptide like insulin that shows extremely low bioavailability through the gastro-intestinal (GIT) route. To address this problem, we have designed a novel drug delivery system (DDS) using precipitation-induced Barium (Ba) salt particles. The DDS can load insulin molecules and transport them through the GIT route. There were several in vitro simulation tests carried out to prove the efficiency of Ba salt particles as oral delivery candidates. All three Ba salt particles (BaSO4, BaSO3, and BaCO3) showed very good loading of insulin (>70% in all formulations) and a degree of resistance throughout a wide range of pHs from basic to acidic conditions when assessed by spectrophotometry. Particles and insulin-associated particles were morphologically assessed and characterized using FE-SEM and FT-IR. A set of tests were designed and carried out with mucin to predict whether the particles are potentially capable of overcoming one of the barriers for crossing intestinal epithelium. The mucin binding experiment demonstrated 60-100% of mucin adhesion to the three different particles. FT-IR identifies the characteristic peaks for mucin protein, particles, and particle-mucin complex re-confirming mucin adhesion to the particles. Finally, the effectiveness of nano-insulin was tested on streptozotocin (STZ) induced diabetic rats. A short acting human insulin analog, insulin aspart, was loaded into Ba salt particles at a dose of 100 IU/Kg prior to oral administration. Among the three formulations, insulin aspart-loaded BaSO4 and BaCO3 particles dramatically reduced the existing hyperglycemia. BaSO4 with loaded Insulin showed an onset of glucose-lowering action within 1 hr, with blood glucose level measured significantly lower compared to the 2nd and 3rd h (p < 0.05). Insulin-loaded BaCO3 particles showed a significant decrease in blood glucose level at 1-2 h, although the glucose level started to show a slight rise at 3rd h and by 4th h, it was back to baseline level. However, although BaSO3 particles with loaded insulin showed a trend of reduction in blood glucose level, the reduction was not found to be significant (p < 0.05) at any point in time. Therefore, oral formulations of insulin/BaSO4 and insulin/BaCO3 particles were observed as effective as native insulin aspart subcutaneous formulation in terms of onset and duration of action. Further investigation will be needed to reveal bioavailability and mechanism of action of this novel Nano-Insulin formulations.

Matched MeSH terms: Biological Availability
Fulltext Pharmacokinetics and Biodistribution of Thymoquinone-loaded Nanostructured Lipid Carrier After Oral and Intravenous Administration into Rats

Zakarial Ansar FH, Latifah SY, Wan Kamal WHB, Khong KC, Ng Y, Foong JN, et al.

Int J Nanomedicine, 2020;15:7703-7717.
PMID: 33116496 DOI: 10.2147/IJN.S262395

Background: Thymoquinone (TQ), an active compound isolated from Nigella sativa, has been proven to exhibit various biological properties such as antioxidant. Although oral delivery of TQ is valuable, it is limited by poor oral bioavailability and low solubility. Recently, TQ-loaded nanostructured lipid carrier (TQ-NLC) was formulated with the aim of overcoming the limitations. TQ-NLC was successfully synthesized by the high-pressure homogenization method with remarkable physiochemical properties whereby the particle size is less than 100 nm, improved encapsulation efficiency and is stable up to 24 months of storage. Nevertheless, the pharmacokinetics and biodistribution of TQ-NLC have not been studied. This study determined the bioavailability of oral and intravenous administration of thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) in rats and its distribution to organs.
Materials and Methods: TQ-NLC was radiolabeled with technetium-99m before the administration to the rats. The biodistribution and pharmacokinetics parameters were then evaluated at various time points. The rats were imaged at time intervals and the percentage of the injected dose/gram (%ID/g) in blood and each organ was analyzed.
Results: Oral administration of TQ-NLC exhibited greater relative bioavailability compared to intravenous administration. It is postulated that the movement of TQ-NLC through the intestinal lymphatic system bypasses the first metabolism and therefore enhances the relative bioavailability. However, oral administration has a slower absorption rate compared to intravenous administration where the AUC0-∞ was 4.539 times lower than the latter.
Conclusion: TQ-NLC had better absorption when administered intravenously compared to oral administration. However, oral administration showed greater bioavailability compared to the intravenous route. This study provides the pharmacokinetics and biodistribution profile of TQ-NLC in vivo which is useful to assist researchers in clinical use.

Matched MeSH terms: Biological Availability
Fulltext Assessment of heavy metal pollution in the straits of Johore by using transplanted caged mussel, Perna viridis

Zakaria, M.P., Yap, C.K., Eugene Ng, Y.J., Tan, S.G.

Pertanika Journal of Science & Technology, 2013;21(1):75-96.
MyJurnal

In this study, a polluted site at Kg. Pasir Puteh was assessed for heavy metal pollution by using
transplanted caged mussel (Perna viridis) from a relatively clean population, Sg. Melayu; both are located in the Strait of Johore. For control purposes, the P. viridis from Kg. Pasir Puteh were also simultaneously transplanted in Sg. Melayu at the same time. It was found that Zn was the metal which got accumulated fastest in the transplanted mussel while Cd was the slowest. This study indicated that the byssus of Perna viridis was most effective for biomonitoring of Cd, Ni, Pb and Zn, while the shell could be used for the biomonitoring of Cu, Ni and Pb and the total soft tissue for the biomonitoring of Ni since they were able to accumulate and eliminate the respective metals well. By using mussel as a biomonitor, the present study found that Kg. Pasir Puteh, which is located in the eastern part of the Strait of Johore, had significantly higher contamination and bioavailabilities of Cd, Cu, Fe, Ni, Pb and Zn. Therefore, the use of the transplanted caged mussels is very useful for heavy metal assessment purposes since it can increase the validity of data interpretation by minimizing ecological factors.

Matched MeSH terms: Biological Availability
Cetyltrimethylammonium bromide-nanocrystalline cellulose (CTAB-NCC) based microemulsions for enhancement of topical delivery of curcumin

Zainuddin N, Ahmad I, Zulfakar MH, Kargarzadeh H, Ramli S

Carbohydr Polym, 2021 Feb 15;254:117401.
PMID: 33357890 DOI: 10.1016/j.carbpol.2020.117401

Low bioavailability and poor water solubility have limited the utilization of curcumin in conventional dosing methods. As an alternative, microemulsions as drug carrier can improve curcumin delivery. A cetyltrimethylammonium bromide-nanocrystalline cellulose (CTAB-NCC)-based microemulsion was developed and its potential use as a topical delivery method for curcumin was investigated. The effect of microemulsion's particle size and its microstructure as well as the presence of the CTAB-NCC nanoparticle on the topical delivery of curcumin was studied. In vitro permeation studies showed higher penetration rate of curcumin from the oil-in-water type-microemulsions. The skin permeation profile of curcumin followed Higuchi release kinetics. Furthermore, use of the (CTAB-NCC)-based microemulsion enhanced curcumin accumulation in the skin and these system showed non cytotoxicity effect on L929 cell line. These results showed the potential of (CTAB-NCC)-based microemulsions as controlled-release topical systems for the delivery of curcumin and potentially other lipophilic drugs.

Matched MeSH terms: Biological Availability
Fulltext Comparative bioavailability study of two ketoconazole tablet preparations

Yuen KH, Wong JW, Billa N, Choy WP, Julianto T

Med J Malaysia, 1999 Dec;54(4):482-6.
PMID: 11072466

The bioavailability of a generic preparation of ketoconazole (Zorinax from Xepa-Soul Pattinson, Malaysia) was evaluated in comparison with the innovator product (Nizoral from Janssen Pharmaceutica, Switzerland). Eighteen healthy male volunteers participated in the study conducted according to a two-way crossover design. The bioavailability was compared using the parameters, total 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 values of the two products in all the three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity and Cmax values of Zorinax over Nizoral was found to lie between 0.82-1.04 and 0.83-1.02, respectively, being within the acceptable equivalence limit of 0.80-1.25. These findings indicate that the two preparations are comparable in the extent and rate of absorption. In addition, the elimination rate constant (ke) and apparent volume of distribution (Vd) were calculated. For both parameters, there was no statistically significant difference between the values obtained from the data of the two preparations. Moreover, the values are comparable to those reported in the literature.

Matched MeSH terms: Biological Availability
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: Biological Availability
Simple high-performance liquid chromatographic method for determination of ketoconazole in human plasma

Yuen KH, Peh KK

J Chromatogr B Biomed Sci Appl, 1998 Sep 18;715(2):436-40.
PMID: 9792531

A simple high-performance liquid chromatographic method using fluorescence detection was developed for the determination of ketoconazole in human plasma. The method entailed direct injection of the plasma sample after deproteinization using acetonitrile. The mobile phase comprised 0.05 M disodium hydrogen orthophosphate and acetonitrile (50:50, v/v) adjusted to pH 6. Analysis was run at a flow-rate of 1.5 ml/min with the detector operating at an excitation wavelength of 260 nm and an emission wavelength of 375 nm. The method is specific and sensitive with a quantification limit of approximately 60 ng/ml and a detection limit of 40 ng/ml at a signal-to-noise ratio of 3:1. Mean absolute recovery value was about 105%, while the within-day and between-day coefficient of variation and percent error values of the assay method were all less than 14%. The calibration curve was linear over a concentration range of 62.5-8000 ng/ml.

Matched MeSH terms: Biological Availability
In vivo/in vitro correlation of experimental sustained-release theophylline formulations

Yuen KH, Desmukh AA, Newton JM

Pharm Res, 1993 Apr;10(4):588-92.
PMID: 8483843

A novel multiparticulate sustained-release theophylline formulation, which consisted of spherical drug pellets coated with a rate-controlling membrane, was evaluated in vivo. Two preparations that differ solely in the coat thickness, and hence rate of in vitro drug release, were studied in comparison with a solution of the drug. Both preparations produced serum concentration profiles that are reflective of a slow and sustained rate of absorption. The in vivo release versus time profiles calculated using a deconvolution procedure showed that the two preparations differed in the rate but not the extent of drug release. Satisfactory correlation was also obtained between the in vivo and the in vitro results. When the two preparations were further compared using the parameters, time to reach peak concentration (Tp), peak concentration (Cp), and total area under the serum concentration versus time curves (AUC), a statistically significant difference was observed in the Tp and Cp values but not the AUC values, suggesting that the preparations differed in the rate but not the extent of absorption. In addition, the extent of absorption from both preparations was comparable to that obtained with the drug solution.

Matched MeSH terms: Biological Availability
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: Biological Availability
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: Biological Availability
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: Biological Availability
Fulltext Immunomodulatory Effects and Mechanisms of Curcuma Species and Their Bioactive Compounds: A Review

Yuandani, Jantan I, Rohani AS, Sumantri IB

Front Pharmacol, 2021;12:643119.
PMID: 33995049 DOI: 10.3389/fphar.2021.643119

Curcuma species (family: Zingiberaceae) are widely utilized in traditional medicine to treat diverse immune-related disorders. There have been many scientific studies on their immunomodulating effects to support their ethnopharmacological uses. In this review, the efficacy of six Curcuma species, namely, C. longa L., C. zanthorrhiza Roxb., C. mangga Valeton & Zijp, C. aeruginosa Roxb. C. zedoaria (Christm.) Roscoe, and C. amada Roxb., and their bioactive metabolites to modulate the immune system, their mechanistic effects, and their potential to be developed into effective and safe immunomodulatory agents are highlighted. Literature search has been carried out extensively to gather significant findings on immunomodulating activities of these plants. The immunomodulatory effects of Curcuma species were critically analyzed, and future research strategies and appropriate perspectives on the plants as source of new immunomodulators were discussed. Most of the pharmacological investigations to evaluate their immunomodulatory effects were in vivo and in vitro experiments on the crude extracts of the plants. The extracts were not chemically characterized or standardized. Of all the Curcuma species investigated, the immunomodulatory effects of C. longa were the most studied. Most of the bioactive metabolites responsible for the immunomodulating activities were not determined, and mechanistic studies to understand the underlying mechanisms were scanty. There are limited clinical studies to confirm their efficacy in human. Of all the bioactive metabolites, only curcumin is undergoing extensive clinical trials based on its anti-inflammatory properties and main use as an adjuvant for the treatment of cancer. More in-depth studies to understand the underlying mechanisms using experimental in vivo animal models of immune-related disorders and elaborate bioavailability, preclinical pharmacokinetics, and toxicity studies are required before clinical trials can be pursued for development into immunomodulatory agents.

Matched MeSH terms: Biological Availability
Fulltext In vitro bioaccessibility and antioxidant properties of edible bird's nest following simulated human gastro-intestinal digestion

Yida Z, Imam MU, Ismail M

BMC Complement Altern Med, 2014;14:468.
PMID: 25475744 DOI: 10.1186/1472-6882-14-468

Edible birds' nest (EBN) is reported to be antioxidant-rich. However, the fate of its antioxidants after oral consumption is not yet reported. To explore this, we hypothesized that EBN antioxidants are released from their matrix when subjected to in vitro simulated gastrointestinal digestion.

Matched MeSH terms: Biological Availability
Fulltext Bioactive molecules: current trends in discovery, synthesis, delivery and testing

Yew Beng Kang, Pichika R Mallikarjuna, Davamani A Fabian, Adinarayana Gorajana, Chooi Ling Lim, Eng Lai Tan

International e-Journal of Science, Medicine & Education, 2013;7(11):32-46.
MyJurnal

Important bioactive molecules are molecules that are pharmacologically active derived from natural sources and through chemical synthesis. Over the years many of such molecules have been discovered through bioprospective endeavours. The discovery of taxol from the pacific yew tree bark that has the ability in stabilising cellular microtubules represents one of the hallmarks of success of such endeavours. In recent years, the discovery process has been aided by the rapid development
of techniques and technologies in chemistry and biotechnology. The progress in advanced genetics and computational biology has also transformed the way hypotheses are formulated as well as the strategies for drug discovery. Of equal importance is the use of advanced drug delivery vehicles in enhancing the efficacy and bioavailability of bioactive molecules. The availability of suitable animal models for testing and validation is yet another major determinant in increasing the prospect for
clinical trials of bioactive molecules.

Matched MeSH terms: Biological Availability
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: Biological Availability
Influence of route of administration on the absorption and disposition of alpha-, gamma- and delta-tocotrienols in rats

Yap SP, Yuen KH, Lim AB

J Pharm Pharmacol, 2003 Jan;55(1):53-8.
PMID: 12625867

A study was conducted to evaluate the bioavailability of alpha-, gamma- and delta-tocotrienols administered via oral, intravenous, intramuscular and intraperitoneal routes in rats. Three separate experiments, each conducted according to a two-way crossover design, were carried out to compare intravenous and oral, intramuscular and oral, and intraperitoneal and oral administration. Oral absorption of all three tocotrienols was found to be incomplete. Of the three tocotrienols, alpha-tocotrienol had the highest oral bioavailability, at about 27.7+/-9.2%, compared with gamma- and delta-tocotrienols, which had values of 9.1+/-2.4% and 8.5+/-3.5%, respectively. Such biodiscrimination was also observed in their total clearance rates (estimated from the intravenous data). alpha-Tocotrienol showed the lowest clearance rate at about 0.16 L kg(-1) h(-1), whereas that of delta- and gamma-tocotrienols was quite similar, with values of 0.24 and 0.23 L kg(-1) h(-1), respectively. Interestingly, all three tocotrienols were found to be negligibly absorbed when administered intraperitoneally and intramuscularly. Thus, these two routes of administration should be avoided when evaluating the biological activities of the tocotrienols in whole animal experiments.

Matched MeSH terms: Biological Availability
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: Biological Availability
Fulltext Pharmacokinetics of Naja sumatrana (equatorial spitting cobra) venom and its major toxins in experimentally envenomed rabbits

Yap MK, Tan NH, Sim SM, Fung SY, Tan CH

PLoS Negl Trop Dis, 2014 Jun;8(6):e2890.
PMID: 24901441 DOI: 10.1371/journal.pntd.0002890

BACKGROUND: The optimization of snakebite management and the use of antivenom depend greatly on the knowledge of the venom's composition as well as its pharmacokinetics. To date, however, pharmacokinetic reports on cobra venoms and their toxins are still relatively limited. In the present study, we investigated the pharmacokinetics of Naja sumatrana (Equatorial spitting cobra) venom and its major toxins (phospholipase A2, neurotoxin and cardiotoxin), following intravenous and intramuscular administration into rabbits.
PRINCIPAL FINDINGS: The serum antigen concentration-time profile of the N. sumatrana venom and its major toxins injected intravenously fitted a two-compartment model of pharmacokinetics. The systemic clearance (91.3 ml/h), terminal phase half-life (13.6 h) and systemic bioavailability (41.9%) of N. sumatrana venom injected intramuscularly were similar to those of N. sputatrix venom determined in an earlier study. The venom neurotoxin and cardiotoxin reached their peak concentrations within 30 min following intramuscular injection, relatively faster than the phospholipase A2 and whole venom (Tmax=2 h and 1 h, respectively). Rapid absorption of the neurotoxin and cardiotoxin from the injection site into systemic circulation indicates fast onsets of action of these principal toxins that are responsible for the early systemic manifestation of envenoming. The more prominent role of the neurotoxin in N. sumatrana systemic envenoming is further supported by its significantly higher intramuscular bioavailability (Fi.m.=81.5%) compared to that of the phospholipase A2 (Fi.m.=68.6%) or cardiotoxin (Fi.m.=45.6%). The incomplete absorption of the phospholipase A2 and cardiotoxin may infer the toxins' affinities for tissues at the injection site and their pathological roles in local tissue damages through synergistic interactions.
CONCLUSION/SIGNIFICANCE: Our results suggest that the venom neurotoxin is absorbed very rapidly and has the highest bioavailability following intramuscular injection, supporting its role as the principal toxin in systemic envenoming.

Matched MeSH terms: Biological Availability

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