Average Bioavailability Research Articles

Determinação da Biodisponibilidade da Lisina Sulfato e Lisina HCl com Frangos de Corte

Com o objetivo de determinar a biodisponibilidade de duas fontes de lisina (lisina HCl e lisina sulfato), por intermédio de um ensaio de crescimento, foram alojados em um galpão de alvenaria com 56 boxes 840 pintos de corte machos com um dia de idade. Duas dietas basais foram formuladas para atender as exigências nutricionais das aves nas fases inicial e crescimento, deficientes apenas em lisina e suplementadas em 0,08; 0,16; e 0,24% pelas duas fontes de lisina. As variáveis avaliadas foram: ganho de peso, consumo de ração, conversão alimentar, rendimento de carcaça, rendimento de perna, rendimento de peito, rendimento de filé e porcentagem de gordura abdominal. Com os dados obtidos foram estimadas equações de regressão linear múltipla e, usando os coeficientes de regressão destas, foi determinada a biodisponibilidade da lisina sulfato em relação a lisina HCl, padronizada como 100% disponível. As equações obtidas que melhor estimaram a biodisponibilidade das lisinas foram Y = 544,72 + 439,62 X1 + 475,84 X2, R² = 0,90, para ganho de peso de 01 a 21 dias de idade, Y = 1824,63 + 1469,18 X1 + 1381,33 X2, R² = 0,85, para ganho de peso de 01 a 42 dias de idade, Y = 1,9623 - 0,9043X1--1,0235 X2, R² = 0,83, para conversão alimentar de 01 a 21 dias de idade, Y = 0,3766 + 0,5320 X1 + 0,4986 X2, R² = 0,88, para peso de peito aos 42 dias de idade e Y = 0,2565 + 0,4685X1 + 0,4300 X2, R² = 0,92, para peso de filé de peito aos 42 dias de idade das aves. A biodisponibilidade média encontrada para a Lisina Sulfato foi de 100,19%, mostrando não haver diferença significativa na biodisponibilidade das lisinas testadas.

Effects of time and dietary iron on tissue iron concentration as an estimate of relative bioavailability of supplemental iron sources for ruminants

Two experiments were conducted to investigate the effects of time and dietary Fe on tissue Fe concentrations following short-term, high level supplementation for use as a bioassay procedure for supplemental Fe sources for ruminants. In Experiment 1, 28 wethers were allotted randomly to four experimental diets which were fed for 15 or 30 days. The basal maize–soyabean meal–cottonseed hulls diet (193 mg kg −1 Fe) was supplemented with 0, 400, 800 or1200 mg kg −1 added Fe from reagent grade ferrous sulfate (FeSO 4 ·7H 2 O). Iron concentrations in liver, kidney, and spleen increased ( P <0.05) as dietary Fe increased; however, muscle, heart, and bone Fe concentrations were unaffected. A logarithmic transformation of liver or kidney Fe concentrations at 30 days regressed on added dietary Fe produced the best fits to a linear model. In Experiment 2, bioavailability of Fe from three feed grade ferrous carbonates known to differ (carbonates A, B, and C) was compared to that from reagent grade ferrous sulfate. The dietary treatments fed for 30 days included the above basal diet (90 mg kg −1 Fe) supplemented with 0, 300, 600 or 900 mg kg −1 added Fe from ferrous sulfate or 600 mg kg −1 Fe from ferrous carbonates A, B, or C. Liver Fe concentrations from sheep fed ferrous sulfate were numerically greater than those of animals fed the carbonate sources or control diet. Kidney Fe concentrations from lambs fed ferrous sulfate at 600 mg kg −1 Fe or carbonate-A were greater ( P <0.05) than those fed carbonates B or C. Iron concentrations in spleen were lower ( P <0.05) in lambs fed carbonate-B than for those fed 600 mg kg −1 Fe as ferrous sulfate, but were similar to other carbonates. Overall average bioavailability estimates based on multiple regression slope ratios for the three tissues were ferrous sulfate 1.00, carbonate-A 0.55, carbonate-B 0.00, and carbonate-C 0.20. Estimates for carbonates A and C were similar to those based on hemoglobin concentrations reported previously for young swine supplemented at dietary concentrations near the requirement.

Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: A phase I study

The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drug's use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from <10% to virtually 100%. Further, the 2-hour infusion of i.v. Bu gave a time to maximum plasma concentration following drug administration similar to that of oral Bu (2 hours and 1.8 hours, respectively), and i.v. Bu had a clearance similar to that of oral Bu. Based on the data in this study, we suggest that the optimal (starting) dose of i.v. Bu (in combination with Cy) in our forthcoming phase 2 trial should be on the order of 0.8 mg/kg to target an area under the curve (AUC) of 1100 to 1200 micromol/L per minute. This would secure myeloablation and engraftment but save the vast majority of patients from the increased risk of serious hepatic veno-occlusive disease that has been reported when the AUC level exceeds 1500 micromol/L per minute. Bu administration via the i.v. route will assure complete bioavailability and reliable systemic drug exposure with more predictable blood levels and, therefore, possibly lower the risks for serious/life-threatening toxicity, graft rejection, and recurrent leukemia. Biol Blood Marrow Transplant 2000;6(5A):548-54.

Introduction

Introduction

Estimated relative bioavailability of supplemental inorganic molybdenum sources and their effect on tissue molybdenum and copper concentrations in lambs

Forty crossbred wether lambs, 44 kg initial body weight, were used to study relative bioavailability of Mo in supplemental Mo sources and their effects on body Cu storage. The basal maize-soya-bean meal-cottonseed hulls diet contained 11.5 mg kg −1 Cu, 1.1 mg kg −1 Mo and 2.1 g kg −1 S (DM basis) and was supplemented with 0, 15, 30, or 45 mg kg −1 (as-fed basis) added Mo as reagent grade sodium molybdate as the standard, or 30 mg kg −1 added Mo as ammonium molybdate, molybdenum trioxide, or molybdenum metal. Diets were fed for 28 days and feces and urine were collected for the last 5 days and composited by lamb. At the end of the trial, serum, liver, kidney, muscle, and bile were collected and analyzed for Mo and Cu. Based on multiple regression slope ratios of tissue concentration or daily excretion (including that from bile) of Mo on added dietary Mo concentration, the average relative bioavailability values were 1.00, 1.04, 1.10 and 0.18 for sodium molybdate, ammonium molybdate, molybdenum trioxide, and molybdenum metal. Serum and muscle Mo concentrations had the best fits to a linear model. Kidney Cu, serum total Cu, serum TCA-insoluble Cu, and fecal Cu concentrations increased with increasing dietary intakes of Mo.

Individual Bioequivalence—A Review of the FDA Draft Guidance

As more generic drugs become available in the marketplace, it is a public concern whether the quality, safety, and efficacy of generic drugs are the same as the brand name drug. Under current regulation, the United States Food and Drug Administration (FDA) only requires that evidence of bioequivalence in average bioavailability be provided for assessment of bioequivalence. FDA, however, does not require that bioequivalence among generic copies of the same brand name drug be demonstrated. As a result, it is a concern whether these generic drugs can be used interchangeably. To address this question, the concepts of population bioequivalence for drug prescribability and individual bioequivalence for drug switchability have been proposed. In this paper, we provide a comprehensive review of the draft FDA guidance on “In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches” which was distributed for comment in October 1997. The discussion will be primarily on the FDA proposed criteria, design, statistical methods, and interpretations on the assessment of individual bioequivalence from the pharmaceutical industry perspective.

Estimating the oral bioavailability of methylmercury to channel catfish (Ictalurus punctatus)

AbstractIn classical pharmacology, oral bioavailability of a toxicant is defined as that fraction of an orally administered dose reaching the systemic circulation of the animal. The present study estimates the bioavailability of methylmercury in channel catfish (Ictalurus punctatus) by comparing concentrations in the blood through time after oral and intra‐arterial (IA) administration. Catfish were cannulated in the dorsal aorta and gavaged a pelleted feed that had been spiked with methylmercury. Each catfish was gavaged an increasing amount of spiked feed. Following oral dosing, serial blood samples were removed for more than 1,500 h. One month after removal of the last blood sample, the same fish were injected IA with methylmercury and serial blood samples were removed for more than 3,000 h. The area under the curve of the blood concentration‐time curve extrapolated to infinity (AUC0→∞) was calculated from fish dosed orally and IA using both noncompartmental (trapezoidal) and compartmental methods. Bioavailability was estimated as the ratio of the dose‐corrected oral AUC0→∞ to the IA AUC0→∞. Average bioavailability estimates from this approach were 33% using noncompartmental (range 14–55%) and 29% using compartmental (range 12–42%) methods and were correlated with the amount of food gavaged to the fish (r2 = 0.95, p = 0.026). Bioavailability estimates using the present methods were much lower than estimates using more conventional methods (i.e., assimilation efficiency estimates using mass balance), suggesting that conventional methods may overestimate the true bioavailability of toxicants in fish.

The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria

Eight male Vietnamese malaria patients received 600 mg of artemisinin in a single dose of 3 suppositories containing 200 mg each; 24 h later they received a single oral dose of mefloquine, 15 mg/kg. Plasma artemisinin concentrations were measured until 24 h after dosing, and parasites were counted until none could be detected. Artemisinin concentration versus time curves of all subjects were analysed with model-independent methods. Mean C max was 108 μg/L (SD = 60, range 29–169), mean t lag was 0·3 h ( sd = 0), mean t max was 6·5 h ( sd = 3·9, range 2–14). By comparing the area under the concentration-time curve with that found in a previous study on oral artemisinin, average bioavailability relative to oral administration was estimated to be approximately 30%. Median parasite clearance time was 24 h (range 24–72). We concluded that therapeutic blood concentrations of artemisinin can be reached after rectal administration. There was a large inter-individual variation in blood concentrations attained. The dose given by rectal administration should probably be twice the usual oral dose, i.e., at least 20 mg/kg of body weight twice daily.

Pharmacokinetics of Intravenous and Oral Losartan in Patients with Heart Failure

The pharmacokinetics of a selective AT1-subtype, nonpeptide, orally active, angiotensin II receptor antagonist, losartan, were characterized in 11 patients with heart failure (New York Heart Association class II, n = 6; class III, n = 4; class IV, n = 1) after oral and intravenous administration. In these patients, average plasma clearance of losartan was 566 mL/min, volume of distribution at steady-state was 34 L, and terminal plasma half-life was 1.5 hours. Average bioavailability was 36%. No clinically significant accumulation of losartan or its active metabolite, EXP3174, occurred after multiple-dose oral administration for 7 to 8 days. Terminal plasma half-life of EXP3174 after oral administration of losartan was 7.6 hours. The pharmacokinetics of losartan in patients in this study appear to be similar to those in healthy subjects studied previously.

An Animal Model for Simultaneous Pharmacokinetic/Pharmacodynamic Investigations: Application to Cocaine

An animal model suitable for pharmacokinetic/pharmacodynamic investigations is described. This model allows drug administration via different routes, serial blood sampling, serial brain ECF sampling, and monitoring the cardiovascular functions without touching the animal. This rat model was utilized to study the relationship between cocaine pharmacokinetics and the neurochemical and cardiovascular responses to cocaine administration via different routes. The pharmacokinetic results showed that the average cocaine bioavailability after i.p. administration was 71% and after oral administration was only 19.2%. Cocaine was rapidly distributed into the brain, and the brain ECF/plasma distribution ratio measured as the ratio of the brain ECF AUC to the plasma AUC was 2.02 ± 0.59. The relationship between cocaine brain ECF concentration and the change in dopamine brain ECF concentration was described by the sigmoid E max pharmacodynamic model. When the relationship between cocaine plasma concentration and the change in the cardiovascular functions was examined, hysteresis loops were observed. These hysteresis loops may suggest the existence of an effect compartment for the cardiovascular effects of cocaine or that cocaine metabolites are contributing to cocaine cardiovascular effects. These results indicate that the described animal model is useful in simultaneous pharmacokinetic/pharmacodynamic investigations specifically for studies that involve centrally acting drugs.

High absorbency and subchronic morphologic effects on the nasal epithelium of a nasal insulin powder dosage form with a soybean-derived sterylglucoside mixture in rabbits.

A soybean-derived sterylglucoside mixture (SG) is a potential enhancer of the nasal absorption of insulin. The aim of the study was to examine the absorption of insulin given as the powder dosage form with SG and excipient and to determine the subchronic effects of SG on the morphology of rabbit nasal epithelium. The insulin powder dosage form with SG was administered to the rabbit nasal cavity for five successive days. The average bioavailability and the average pharmacological bioavailability of insulin were about 25.0 and 61.6%, respectively. The nasal mucosa was taken from the nasal cavity and side-effects were investigated using an optiphoto light microscope. The insulin powder dosage form with SG produced no signs of inflammation, erosion or squamous metaplasia. These findings indicate that SG can be considered as a safe and effective enhancer and excipient in the nasal insulin powder dosage form.

Optimal Unbiased Tests for Equivalence in Intrasubject Variability

The equivalence in average bioavailability between formulations may not be sufficient for assessment of bioequivalence. The difference in intrasubject variability between formulations should also be considered. This article presents an unbiased test procedure for equivalence in intrasubject variability of bioavailability that is uniformly more powerful than the two one-sided tests procedure proposed by Liu and Chow. Under a stronger condition, a uniformly most powerful invariant test for this problem is proposed. Some numerical comparisons and an example are also presented.

Tolerance intervals for assessing individual bioequivalence.

Evaluation of equivalence of two formulations of a drug typically entails the comparison of average bioavailabilities. Recently, however, authors have become aware that this may be insufficient to assess individual bioequivalence, that is, interchangeability of formulations on an individual basis. This paper outlines a tolerance interval procedure to assess individual bioequivalence based on a model that includes a subject by formulation interaction. We give methods for several higher-order cross-over designs along with examples.

On the test of liu and chow's procedure for assessing equivalence in variability of bioavailability

Similar to Schuirmann's two one-sided tests procedure for assessment of bioequivalence in average bioavailability (Schuirmann,), Liu and Chow proposed a two one-sided tests procedure for assessment of equivalence of variability of bioavailability. Their procedure is derived based on the correlation between crossover differences and subject totals. In this paper, we examined the performance of their test procedure in terms of its test size and power for various situations where the intersubject variability and the intrasubject variability of the test drug product are relatively larger, similar, and smaller than that of the intrasubject variability of the reference drug product.

On tier method for assessment of individual bioequivalence

The bioavailability and bioequivalence between drug products has become an important subject in drug development. The average bioavailability of the test (T) and the reference (R) products is currently specified in the FDA guidelines to be used for assessing the bioequivalence of the drug products. However, it has been recognized that the safety for the substitution of a reference drug product with a test drug product in patients, whose concentration may have been titrated to a steady efficacious and safe level, could be a concern. Therefore, it is suggested that individual bioequivalence within each subject be assessed to assure the safety of the drug switchability. This paper examines the statistical properties of TIER procedure that Anderson and Hauck (1) proposed to assess individual bioequivalence. It is shown that Anderson and Hauck's procedure could be improved by imposing some distribution assumption such as lognormal distribution for assessment of individual bioequivalence. This paper also compares the relative performance of the individual bioequivalence based on TIER procedure and the average bioequivalence based on two one-sided tests procedure suggested by Schuirmann (2). The relationship between equivalence limits for the improved TIER procedure and average bioequivalence is also examined.

A three-step procedure for assessing bioequivalence in the general mixed model framework.

Bioavailability data arising from a standard two-period cross-over study are routinely analysed to establish bioequivalence between test and reference formulations. Current regulatory guidelines only require evidence of equivalence in average bioavailability for the assessment of bioequivalence. Under normality assumptions, this is achieved by demonstrating equivalence between the formulation means (step 1). However, the equivalence of formulation variances should also be assessed to get evidence of population bioequivalence (step 2), since a difference in variability of bioavailability may also pose significant problems in drug safety and efficacy. On the other hand, even population bioequivalence does not ensure that an individual subject could be expected to respond similarly to the two formulations. Therefore, whenever individual bioequivalence is the ultimate goal, the magnitude of intra-subject correlation should always be examined as the final stage (step 3). In this paper, these three successive concepts of bioequivalence are cast into the general mixed model framework and a stepwise testing procedure for the global assessment of bioequivalence is proposed. In addition to this, important issues addressed in the regulatory guidelines, such as verification of the model assumptions and application of the log-transformation, are discussed. Lastly, an example is presented to illustrate the proposed three-step procedure on the original and log-transformed scale of measurement.

PHARMACOKINETICS OF HIGENAMINE IN RABBITS

The pharmacokinetics of higenamine were investigated in rabbits by IV bolus, PO route, and IV infusion. Plasma higenamine concentration declined rapidly in a biexponential pattern, with a terminal half-life of 22 min. The AUC increased proportionally with increasing dose, whereas the percentage of unchanged higenamine excreted from urine remained constant when dose was increased. The means of total body clearance, mean residence time, volume of distribution at steady state, and fraction of urinary excretion were 127·7 mL min−1 kg−1, 9·28 min, 1·44 L kg−1, and 5·48%, respectively. The mean percentage of protein binding of higenamine in plasma was 54·8% at steady state after IV infusion. The results from post-infusion also confirmed that higenamine followed a two-compartment open model in animals. After oral administration, higenamine was rapidly absorbed to reach peak concentration within 10 min. Interestingly, the plasma concentration–time profiles revealed two distinguishable groups with different Cmax, extent of absorption, and urinary excretion. The average absolute bioavailabilities of higenamine calculated by AUCs and accumulated urinary excretion were 21·86 and 2·84% versus 20·19 and 5·50% for the two groups, respectively. Upon hydrolysis of urine samples with μ-glucuronidase, urinary concentrations of higenamine were greatly enhanced in both groups

Pharmacokinetics of higenamine in rabbits.

The pharmacokinetics of higenamine were investigated in rabbits by IV bolus, PO route, and IV infusion. Plasma higenamine concentration declined rapidly in a biexponential pattern, with a terminal half-life of 22 min. The AUC increased proportionally with increasing dose, whereas the percentage of unchanged higenamine excreted from urine remained constant when dose was increased. The means of total body clearance, mean residence time, volume of distribution at steady state, and fraction of urinary excretion were 127.7 mL min-1 kg-1, 9.28 min, 1.44 kg-1, and 5.48%, respectively. The mean percentage of protein binding of higenamine in plasma was 54.8% at steady state after IV infusion. The results from post-infusion also confirmed that higenamine followed a two-compartment open model in animals. After oral administration, higenamine was rapidly absorbed to reach peak concentration within 10 min. Interestingly, the plasma concentration-time profiles revealed two distinguishable groups with different Cmax, extent of absorption, and urinary excretion. The average absolute bioavailabilities of higenamine calculated by AUCs and accumulated urinary excretion were 21.86 and 2.84% versus 20.19 and 5.50% for the two groups, respectively. Upon hydrolysis of urine samples with beta-glucuronidase, urinary concentrations of higenamine were greatly enhanced in both groups.

A Confidence Region Approach for Assessing Equivalence in Variability of Bioavailability

AbstractThe problem for assessment of equivalence in variability of bioavailability between two drug products is considered. Similar to the method for assessing bioequivalence in average bioavailability proposed by Chow and Shao (1990), an exact confidence region approach is derived when the intersubject variance is known. When the intersubject variance is unknown, a large sample approximation is considered. The proposed method for assessing equivalence of variability of bioavailability appears to be asymptotically uncorrelated with that of Chow and Shao (1990) for average bioavailability. As a result, the proposed method in conjunction with the method proposed by Chow and Shao (1990) constitutes a confidence region approach for assessing population bioequivalence. An example concerning a bioequivalence trial with 24 healthy volunteers is provided to illustrate the proposed method.

Estimation of the relative bioavailability of inorganic copper sources for sheep

Three experiments were conducted with sheep to assess the relative bioavailability of copper (Cu) in supplemental Cu sources by measuring liver uptake of Cu. In all experiments an initial liver biopsy was taken and then experimental diets were fed for 10 days. In Experiment 1, body Cu stores were depleted by twice weekly intravenous injection for 3 weeks with ammonium tetrathiomolybdate before liver biopsies were taken. Dietary treatments were the basal diet (8.7 mg/kg Cu) supplemented with 0, 20, 40, 60 or 80 mg/kg Cu as reagent grade cupric acetate (standard) or 60 mg/kg Cu as feed grade cupric oxide, sulfate or carbonate. In Experiment 2, the basal diet (8.3 mg/kg Cu) was supplemented with 0, 60, 120 or 180 mg/kg Cu from the standard, reagent grade cupric chloride or 120 mg/kg Cu from feed grade cupric oxide, sulfate or carbonate. In Experiment 3, the basal diet (12.6 mg/kg Cu) was supplemented with 0, 60, 120 or 180 mg/kg as reagent grade cupric chloride (standard) or 120 mg/kg Cu as reagent grade cupric acetate, or feed grade cupric oxide or sulfate. At the end of the three experiments, lambs were killed and livers frozen for Cu analysis. Average relative bioavailability values from Experiments 2 and 3 based on multiple linear regression of liver Cu concentration on added dietary Cu concentration with the initial biopsy Cu as a covariate were 100, 93, 142, 121, and 35 from cupric chloride, acetate, sulfate, carbonate and oxide, respectively.