Information on drug metabolism and pharmacokinetics from World Congress of Pharmacy and Pharmaceutical Sciences 2003
World Congress of Pharmacy and Pharmaceutical Sciences 63rd International Congress of International Pharmaceutical Federation (FIP) hold in Sydney, Australia on September 5-9, 2003. 27 papers were presented about pharmacokinetics and drug metabolism, and bioavailability and bioequivalence. Here, Abstracts of the selected papers are introduced for information on drug metabolism and pharmacokinetics studies.
Issues and challenges in bioequivalence
Midha KK et al. Bioequivalence issues: Discussion and delineation of approaches to resolution A number of important issues in bioequivalence remain unresolved despite more than a decade of research attempting to address them. In this presentation, authors shall give an overview of approaches to a number of these issues and make some suggestions for their resolution based on scientific rationales. The question of highly variable drugs and highly variable drug products remains an issue of contention because these are usually safe drugs with high within-subject variability and large numbers of subjects are required to assess their bioequivalence. The opposite situation applies to narrow therapeutic range drugs where the within-subject variabilityis usually low, but the drugs have sleep dose response curves and the difference between therapeutic and toxic plasma concentrations is relatively small. Options that have been considered include reducing the consumer risk from 5% to 2.5% the use of reduced bioequivalence limits of 90-111%. Authors shall make some observations based on data and simulations. The role of metabolites in bioequivalence studies also remains a controversial issue. In simple cases, such as the administration of an inactive prodrug, bioequivalence is usually assessed based on the active metabolite. The metabolism of many drugs is complex, however, with the formulation of both phase I and phase II metabolites. Authors suggest how an a priori decision to use parent or metabolite data can be based on available pharmacokinetic data combined with results from simulation studies and common sense. Finally, authors shall address the issue of bioequivalence of
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dosage forms containing endogenous compounds such as hormones where the presence of of baseline levels of the hormone may be complicated by circadian rhythmicity, as is the case with thyroid hormones for example.
Wilson RD. Issues and challenges in buioequivalence evalution in Australia and new Zealand The presentation was included a brief overview and discussion of the following topics: the international important of bioequivalence testing in the development and regulation of innovative and generic medicines; the evolution and current state of bioequivalence policies and guidelines in Australia and New Zealand; the use of bioequivalence data in regulatory risk management; the strengths and limitations of current approaches to bioequivalence testing; prescribability and interchangeability; and the practical implication of the possible formation of a joint Australia and New Zealand regulatory authority and the development of a single trans-traman market for pharmaceuticals.
Dressman JB. Issues and challenges in dissolution/in vitro release of drug products Poor drug dissolution, drug decomposition, low permeability through the gut wall and first pass metabolism are the main limitations to oral drug bioavailability. When slow dissolution is the primary limitation to oral drug bioavailability, biorelevant dissolution test can play a pivotal role in optimizing dosage form from development and dosing conditions. Biorelevant dissolution test are those based on the physiological conditions encountered by the drug/dosage form as it moves through the gastrointestinal tract. Separate tests have been
designed to refluct lumenal conditions in the upper gastrointestinal tract after administration of the dosage form in the fasted and fed states, thus enabling the prediction of food effects as well as assessing the relative merits of various candidate dosage forms. Although satisfactory conditions have been identified for modeling the stomach and small intestine in the fasted state, there are still some improvements to be made for the fed state. Recent expansion of biorelevant tests to simulate release from oral dosage forms with modified release patterns mandates consideration of passage times and conditions not only in the stomach and jejunum, but also in the ileum and proximal colon. A further challenge lies in the lack of data applicable to designed media to simulate cononic conditions. A further issue is the application of dissolution testing to assessment of generic drug products. The biopharmaceutical classification system already enables biowaivers for immediate release drug products containing class I drugs and the question is whether dissolution testing could also be used as a surrogate for pharmacokinetic studies for class III and II drugs.
Evans AM. In vitro-in vivo correlations in the design and evaluation of oral dosage form Dissolution testing is the most valuable of the in vitro quality control tests for oral dosage forms, and regulatory bodies place great importance in the results of dissolution testing during the registration of new formulations. The development of an appropriate dissolution test for quality control purpose must take into consideration the choice of apparatus, fluid volume, agitation conditions and dissolution medium together with sampling times and specification limit. In vitro dissolution testing is also being used, increasingly, as an alternative to in vivo studies for the registration of certain solid oral dosage forms. For an immediate release solid oral dosage form of a drug that has linear pharmacokinetics, good aqueous solubility, good biological membrane permeation, and high absolute bioavailability, dissolution data can in some circumstances be used as a substitute for a bioequivalence study in humans. For modified- release oral dosage formulations, dissolution testing is used to guide formulation development, to identify critical manufacturing variables, and to establish valuable in vitro-in vivo correlations. These correlations can be used, in some circumstances, to
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obtain a waiver for further bioavailability studies. The most useful in vitro-in vivo correlations is a level A correlation, which is defined as a direct 1-to-1 relationship between the % absorbed in vivo and the % dissolved in vitro. The development and validation of such correlations will be discussed together with examples of how in vitro-in vivo correlations have been used to support the design, development and registration of modified-release solid oral forms. in vitro-in vivo correlations can be used to design a solid oral dosage form that will give a designed plasma concentration versus time profile.
Shah VP. Biopharmaceutics classification system-What progress have we made? Biopharmaceutics classification system (BCS) is a scientific fraework for classifying drug substance based on its aqueous solubility and intestinal permeability. It is used as a drug development tool and can be used justify biowaiver. BCS provides a basis for expecting and establishing in vivo correlations. BCS guidance is based on solubility and permeability (bioavailability) of the drug substance and dissolution of the drug products. Immediate release oral dosage forms with highly soluble and highly permeable drug substance and with rapid dissolution are classified as BCS Class I drug products, and waived from requiring bio-studies. This judgement is also based on risk assessment that products are of low risk category. In these cases, dissolution is used as a surrogate marker for blood level determination. Based on dissolutions at several symposia and workshops, it is concluded that the current BCS guidance is too rigid and conservative. Possible “relaxed” criteria and class boundaries based on underlying of gastrointestinal tract has been discussed as a means to provide biowaivers for immediate release oral drug products . The suggested changes include: extending dissolution time requirement for class I drug, lowering permeability/bioavailability criteria, amending bioavailability criteria for class III drug products with rapid dissolution, narrowing solubility pH range. The greatest challenge of all is harmonization and acceptability of biowaivers for drug products based on BCS.
Traditional medicines
Jiang JX et al. Effect of St john’s Wort and
ginseng on the pharmacokinetics and pharmacodynamics of warfarin. The study on effect of St john’s Wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin .was carried out in an open label, three-treatment, randomized crossover test om tweive male subjects. The data indicated that there is significant difference in warfarin pharmacokinetics and pharmacodynamics in subjects pre-treated with St John’s Wort. But ginseng did not affect pharmacokinetics and pharmacodynamics of warfarin. Both of St John’s Wort and ginseng did not affect warfarin apparent volume of distribution and protein binding. The study conclusion is that St John’s Wort significantly induces the metabolism of S- and R-warfarin and is likely lead to a reduction in warfarin efficacy. Co-administration of warfarin with ginseng did not significantly affect pharmacokinetics and pharmacidynamics of warfarin.
Nishimura NN et al. Inhibitory effect of sho-saiko-to (Xiao Chaihu Tang) on the function of P-glycoprootein in Caco-2 cells. Digoxin was employed as a substrate of P-glycoprotein (P-gp), and effect of sho-saiko-to and the herbal constituents on the digoxintransport across Caco-2 cell monolayers were examined. The bi-directional transport of 3H-digoxin were carried out using caco-2 cell monolayers cultured on a polycarbonate membrane during 21-23 days. The transported amounts of 3H-digoxin were measured by scintillation analysis to estimate apparent permeability coefficients. The MDR1 mRNA was detected by RT-PCR analysis. The basolateral-to-apical transport of digoxin is ascribed to the efflux pump mediated by P-gp in the cultured Caco-2 cells: (1) much faster transport of digoxin in basolateral-to-apical than apical-to- basolateral direction; (2) concentration and metabolic energy dependence in the efflux transport; (3) inhibition of the transport by P-gp substrates such as verapamil, cyclosporin A and vinblastine; (4) expression of MDR1 mRNA in Caco-2 cells. The sho-saiko-to suppressed the basolateral-to-apical transport of digoxin in a concentration dependence manner. Glycyrrhizae radix and Scutellaiae radix which are herbal composing sho-saiko-to significantly decreased the efflux transport of digoxin. Moreover, glycyrrhizic acid, glycyrrhetinic acid and baicallin equally reduced the apparent permeability coefficients of digoxin efflux. There results suggest
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that sho-saiko-to possesses the inhibitory effects for the efflux pump mediated by P-gp in caco-2 cells, and that cure constituents in sho-saiko-to, glycyrrhizic acid, glycyrrhetinic acid and baicallin deeply contribute to the effects.
Hsiu SL et al. Efect of locorice decoction and glycyrrhizin on cyclosporin pharmacokinetics Licorice, the root of Glycyrrhiza spp. (Fabaceae) is the most common herb used in Chinese medicine. Glycyrrhizin is a major and active constituent of licorice. Cyclosporin is an immunosuppressant with marrow therapeutic window and a substrate for P-glycoprotein, the multi-drug efflux transporter. This study investigated the effects of licorice decoction and glycyrrhizin pharmacokinetics. Cyclosporin was orally administered with and without a concomitant of licorice decoction (equivalent to 100 mg·kg-1 of glycyrrhizin) and glycyrrhizin 100 mg·kg-1 to rats. The blood cyclosporin concentrations were determined by a specific nonoclonal fluorescence polarization immunoassay. The experimental result showed that coadministration of glycyrrhizin significantly decreased the Cmax and AUC0-t of cyclosporin by 53% and 64%, respectively, whereas those were not affected by coadministration of licorice decoction. Everted intestine study revealed that the activity of P-glycoprotein was significantly up-regulated by glycyrrhizin, whereas licorice did not affect that. These in vitro results could explain the fact that absorption of cyclosporin was markedly reduced by glycyrrhizin but not by licorice decoction. The complicate constituents contained licorice decoction beside glycyrrhizin might account for the different interactions with cyclosporine. It is suggested that concurrent use of glycyrrhizin with cyclosporine or other medications whose absorption and metabolism are mediated by P-glycoprotein should require close monitoring.
Choi B and choi J. Effect of quercetin on the pharmacokinetics of cyclosporin in human subjects Effect of quercetin on the pharmacokinetic parameters of cyclosporin were determined in 8 healthy volunteers. Cyclosporin concentrations were estimated with whole blood and analyzed by fluorescence polarization immunoassay. After coadministration of cyclosporin 300 mg with quercewtin 100 mg orally administered for 3 days. The AUC of cyclosporin was significantly increased
compared to control group (p<0.05). The been successful in maintaining a sedated state during concentrations of cyclosporin metabolites were general anesthesia. However, pharmacokinetics and
pharmacodynamics of midazolam in hypothermia is significantly decreased after coadministration. Cmax
known. In the study, the effects of hypothermia stage of cyclosporin was significantly higher in quercetin
coadministration group than control group. The on midazolam pharmacokinetics was compared
investigation in cares of hypothermia patients and half-life was prolonged by quercetin coadministration.
The ratio of metabolites and nomo cyclosporin normal themia. This drug administered by concentrations were decreased significantly by intravenous injection or infusion. The total body
clearance of midazolam in hypothermia after iv quercetin coadministration. Based on these results, it
injection was smaller than that in normal-thermia. might be concluded that quercetin may enhanced
Average serum concentration of midazolam in bioavailability of cyclosporin through the inhibition
of cytochrome P450 which are engaged in both hypothermia after infusion was increased from 1500
ng·mL-1 to cyclosporin absorption and metabolism in liver and 6650 ng·mL-1. Furthemore, it was found
gastrointestinal muscusa, respectively. that the existence of body temperature ranges
depended on the change in midazolam levels was Chiang HM et al. metabolic recognized in all cases. The findings indicated pharmacokinetics of isoflavones in Puerariae overdoses of midazolam in hypothermia. This study Radix Puerariae Radix is used in Chinese medicine. may also clarity the pharmacokinetics and It has a rich content of isoflavones such as purearin, pharmacodynamics of midazolam, and facilitates daidzin and daizein. The study investigated the establishement of an optimal dose of this in metabolic pharmacokinetics if isoflavones after oral hypothermia. administration of traditional decoction and commercial extract of Puerariae Radix in rats and Wang YH et al. Increased absorption of humans. The contents of Puerariae Radix, purearin, digoxin caused by coadministration of Citrus daidzin and daizein were determined by gradient herba in pigs. The effects of Citrus herba on the HPLC. The total content of purearin, daidzin and absorption and disposition of digoxin was studied in daizein in traditional decoction of Puerariae Radix pigs. Citri Aurantii Fructus, Critri Auranntii was about 5%. Serum and urine samples were Pericarpium, and Citri Grandis Pericarpium are assayed by HPLC method prior to and after widely used in Chinese medicine. Dogoxin, a cardiac enzymatic hydrolysis with beta-glucuronidase and glycoside with narrow therapeutic range, is a sulfatase, respectively. The results showed that substrate of the multidrug transporter P-glycoprotein. daidzein sulfates were predominant metabolites in the The results indicated that coadministration of Citri blood stream and daizein glucuronides existed in Aurantii Fructus, Critri Auranntii Pericarpium, and lower level. No purarin, daizin and daizein were Citri Grandis Pericarpium significantly elevated the detected in serum and urine. The urinary excretion of Cmax of digoxin by 101%, 55% and 36%, and daizein sulfates and glucuronides can be detected increased the AUC by 30%, 33% and 12%, until 24-36 h. indicating quite long residence time for respectively. Everted rat gut sac study revealed that daizein conjugates. The urinary recovery of daizein Citrus herbal decoction inhibited the activity of sulfates and daizein glucuronides after intake of P-glycoprotein. It suggested that Citrus herbs like commericial extract were significantly lower than grapefruit juice significantly increased the those after traditional decoction containing bioavailability of digoxin. Thesere, careful comparable isoflavone content by 58% and 51%, therapeutic monitoring of digoxin is suggested when respectively. digoxin was coadministered with Citrus herbs.
Reddy SJS and Venkateswarlu V. In vitro Drug interaction
metabolism of citicoline in human plasma
Okano YO et al. Pharmacokinetics of Citicoline is used in the treatment of brain ischemia,
Alzheimer’s disease, Parkinsonism, Glaucoma and midazolam during hypothermia in intensive care
also as a dietary supplement. It undergoes exlensive units patients Midazolam and a few other drugs
first pass metabolism amd heance high doses of administered to intensive care units patients have
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serum and plasma than that of the release of drug citicoline are used in therapy. The aim of the study is
without any proteins. Since the serum lacks the to determine the Vmax and Km values for citicoline
clotting factors that are normally present in plasma using invitro metabolism analysis in human plasma.
The serum samples were analyzed by a HPLC but have been consumed during the process of
coagulation. It indicates that the extent of protein method. High variation in the values of Vmax and
binding is directly proportional to the amount of Km were observed among the healthy volunteers. It
protein. The utilization of this method for estimation is evident from the results that the levels of enzymes
responsible for citicoline metabolism vary from of human fibrinogen is in progress.
volunteer to volunteer. Therefore, the
pharmacokinetics of citicoline and its delivery to Safety and efficacy requirements for the brain will change from person to person. registration of multisource medicies Protein binding Kanfer I et al. Safety and efficacy
requirements for the registration of multisource Reddy MVSP et al. Comparative study of medicies in South Africa The approval of
multisource (generic) medicines by regulatory protein binding of human serum and plasma with
tetracycline Dynamic dialysis method is used for authorities involves the submission of data obtained study of tetracycline protein binding, where egg shell from surrogate measures, such as bioequivalence
proceduresm for solid oral dosage forms intended for membrance used as diffusion layer and the protein -1
systemic action. Acceptance of appropriate data compartment filled with the drug solution (I mg·mL)
requires that specific criteria such as Cmax and AUC of 2ml whichis immersed in 25 mL glass beaker a
meet the limits specified by the particular registration non-protein compartment filled with 20 mL distilled
authority of the country where such products are water. This whole set-up was kept on a magnetic
intended to be marketed. Generally, these limits stirrer and the outer maintained at 35 ºC throughout
the experiment. Samples were collected from require that the AUC and Cmax test/reference ratio lie
within the acceptance interval of 0.0-1.25 calculated non-protein compartment at regular interval;s and
using log transformed data using a 90% confidence replaced with same volume with distilled water. The
interval. Whilst such acceptance criteria do exsit experiment was repeated by using 1 mL of human
between various countries. Recently, new guidelines blood serum. The percentage of drug released was
for bioavailability/ bioequivalence studies have been analyzed by spectrophotometrically at 385 nm. The
developed by the South African regulatory authority, concentration of tetracycline was determined with the
the Medicines Control Council which, amongst help of standard plot. This represents well that the
plasma proteins, serum proteins having the great others, makes provision for highly variable in
bioequivalence studies and describes procedures and affinity towards the drug and bind with it. It is found
conditions for obtaining for waivers for vivo studies. that the release of drug is very less in presence of
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