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Biomedical subjects

M Mayersohn

Publications and source records attributed to M Mayersohn.

At least 37 records · Page 2Linked to original sources

Pharmacokinetics of the aldose reductase inhibitor tolrestat: studies in healthy young and elderly male and female subjects and in subjects with diabetes.

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 micrograms/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship.

Administration, Oral↗

Influence of activated charcoal on the disposition kinetics of methamphetamine enantiomers in the rat following intravenous dosing.

Methamphetamine (MAP) is a central nervous system stimulant that is widely abused by populations of several countries. There is no specific antidote for the treatment of an overdose. Activated charcoal administered orally has been used to enhance the systemic elimination of certain toxic substances via "gastrointestinal dialysis". The results of in vitro studies have shown that MAP can be rapidly adsorbed from solution by activated charcoal. We have evaluated the effect of a single oral dose of activated charcoal on the disposition kinetics of MAP following a short iv infusion. Male Sprague-Dawley rats were given an oral dose of activated charcoal (Actidose-aqua, 1 g/kg) 10 min before a short iv infusion of racemic MAP; whereas the control group was given an equivalent volume of water. Enantiomers of MAP and metabolites in serum and urine were analyzed by an enantiomer-specific method which employed HPLC and detection of a fluorescent derivative. There were no differences in any of the disposition parameters between the two groups. Within each group, the clearance (CLs) of l-MAP was greater than that of d-MAP. However, there were no differences in the steady-state volume of distribution (Vss). The CLs (mL/(min kg)) and Vss (L/kg) values for l- and d-MAP in the control group were (mean +/- SD): 55.8 +/- 20.4, 48.7 +/- 17.9, 2.64 +/- 1.16, and 2.90 +/- 1.36, respectively. The corresponding values in the charcoal-pretreated group were (mean +/- SD): 57.4 +/- 23.4, 51.1 +/- 20.7, 2.79 +/- 1.32, and 2.98 +/- 1.47. These results suggest that oral activated charcoal does not enhance the elimination of MAP from the body.

Animals↗

Characterization of the properties of cocaine in blood: blood clearance, blood to plasma ratio, and plasma protein binding.

As part of a study to examine cocaine disposition and interaction with ethanol, it was necessary to characterize various properties of cocaine in the blood of the experimental animal. All studies were conducted using blood from healthy adult male Sprague-Dawley rats. Cocaine was incubated in whole blood at 37 degrees C at concentrations of 500-4000 ng/mL. The apparent first-order rate constant for cocaine loss was independent of concentration. Blood clearance, calculated assuming blood volume to be 64 mL/kg, was estimated to be 0.056 +/- 0.003 mL/(min.kg); a value considerably smaller than estimates of systemic clearance. The addition of NaF increased the rate of loss to form benzoylecgonine, as a result of increased chemical degradation and as a consequence of increased pH (to pH 8.0 over 30 h). This NaF-enhanced degradation was abolished when NaF was added to blood buffered to pH 7.4. Ethanol had no influence on cocaine degradation, and there was no evidence of cocaethylene (ethylcocaine) formation. Blood to plasma ratios determined in spiked and authentic samples were constant (0.94-1.05 and 0.99-1.03, respectively) and independent of concentration (100-1500 ng/mL) and pH (7.2-7.6). This ratio was not influenced by NaF or ethanol. The unbound fraction (fu) of cocaine determined in spiked plasma varied from 0.62 to 0.63 over the concentration range (75-2025 ng/mL). Ethanol had no effect on binding. The values for fu determined from authentic blood samples taken from rats dosed intravenously with cocaine (10 mg/kg) ranged from 0.67 to 0.69 (over the concentration range 300-1500 ng/mL). Cocaine plasma protein binding was independent of concentration but depended upon plasma pH (fu, 0.765 and 0.486, at pHs 7.0 and 7.8, respectively.

Animals↗

3,3',4,4'-tetrachloroazobenzene absorption, disposition, and metabolism in male Fischer 344 rats.

3,3',4,4'-Tetrachloroazobenzene (TCAB) is a contaminant generated during the synthesis of 3,4-dichloroaniline and 3,4-dichloroaniline-derived pesticides. TCAB is isosteric to 2,3,7,8-tetrachlorodibenzo-p-dioxin and has been shown to bind to the Ah receptor. Following oral administration of [14C]TCAB (3.2 and 32 mg/kg), 39-45% of the dosed radioactivity was excreted into the urine and 53-56% was recovered in the feces within 48 hr. Less than 6% of the dosed radioactivity remained in the tissues examined at 96 hr. After intravenous administration (3.2 mg/kg), 33% of the dose was excreted in the bile during 6 hr. TCAB metabolites in urine were identified using LC/MS. The major metabolites were sulfate ester conjugates of hydroxylated mono- or dichloroaniline derivatives. Some of these metabolites were also acetylated. After intravenous administration, the disappearance of [14C]TCAB from blood was monitored, and the pharmacokinetic profile was consistent with a two-compartment model. Pharmacokinetic parameters reveal that the compound is readily cleared from the blood with a t1/2 of 4.0 hr, clearance of 12.3 ml/min.kg, and an apparent volume of distribution of 4.3 liters/kg. The absolute oral bioavailability was determined to be 30%. The extensive azo reduction of TCAB decreases its systemic absorption after oral administration and thereby limits the amount of parent compound available to interact with the Ah receptor and decreases the Ah receptor-mediated toxicity.

Administration, Oral↗

Antiphencyclidine monoclonal Fab fragments reverse phencyclidine-induced behavioral effects and ataxia in rats.

Antiphencyclidine monoclonal antibody binding fragments (anti-PCP Fab) were studied in rats as a possible treatment for phencyclidine (PCP) overdose. Each male Sprague-Dawley rat (n = 4 per group) received an i.v. dose of 1 mg/kg of PCP followed 5 min later (as toxicity maximized) by one of three treatments in a random cross-over design. The treatments were 1 ml of saline, a nonspecific polyclonal human Fab, or a high affinity (Kd = 1.8 nM) anti-PCP monoclonal Fab. The doses of the nonspecific and anti-PCP Fab were 0.3, 1.0 and 3.0 times the mole equivalent (mol-eq) dose of PCP. Changes in locomotor activity and ataxia were the best indicators of PCP-induced behaviors among several time-dependent behavioral changes that were evaluated. PCP administration followed by saline treatment resulted in increases in locomotor activity and ataxia that declined to base line after 35 to 40 min. Anti-PCP Fab at 1.0 and 3.0 times the mol-eq dose of PCP significantly (P < .05) and rapidly reversed PCP-induced behaviors to base-line values. Although the 0.3 mol-eq dose of Fab appeared to slightly decrease the behavioral toxicity, the effects were not statistically different from controls in most cases. No significant effects on PCP-induced behaviors were observed after any dose of the nonspecific Fab. In addition, pharmacological and immunological specificity were tested further by treatment of MK-801 {(+)-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine-}-induced behavioral effects. MK-801 is a PCP-like, noncompetitive N-methyl-D-aspartate receptor antagonist which is structurally unrelated to PCP. The anti-PCP Fab treatment had no effect on MK-801-induced locomotor activity. These data clearly show that anti-PCP Fab is a specific PCP antagonist that can rapidly reverse PCP-induced behavioral toxicity in the rat.

Animals↗

Absorption and disposition kinetics of 3,3',4,4'-tetrachloroazoxybenzene in the male Fischer 344 rat.

3,3',4,4'-Tetrachloroazoxybenzene (TCAOB) is a structural analog of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). It is formed as a byproduct during the synthesis of industrial products such as herbicides. TCAOB is a ligand for the Ah receptor and, at much higher doses, exhibits toxicities similar to TCDD. Although the reduced in vivo toxicity of TCAOB probably reflects differences in disposition, this study characterized its absorption and disposition kinetics. Male Fischer 344 rats were administered [14C]TCAOB (3.4 or 34 mg/kg p.o., 3.4 mg/kg i.v.), and the excretion of the radiolabel was monitored over 96 hr. After the low and high dose, 35% and 30% of the [14C]TCAOB were eliminated in the urine, with 55% and 54% eliminated in the feces. At 96 hr, the adipose tissue:blood ratios of [14C]TCAOB equivalents were 8 and 26 for the low and high doses, respectively. After the intravenous dose of TCAOB, the adipose tissue:blood ratio was 21 at 96 hr. Other tissue:blood ratios were of little significance (0.06-3.2). Pharmacokinetic parameters indicate that the parent molecule is cleared from blood with an average half-life of 7 hr and an average clearance of 11 ml/min.kg. Absolute bioavailability was calculated to be approximately 9%. Urine contained a variety of dichlorolaniline conjugates, which support the importance of azo reduction in the disposition of TCAOB. When compared with TCDD, the absorption of TCAOB is greatly reduced and the elimination of metabolites greatly enhanced. Therefore, at equal molar oral doses, TCAOB would express lower levels of Ah receptor-mediated toxicity than those defined for TCDD.

Absorption↗

Pharmacokinetics of amphotericin B in rats as a function of dose following constant-rate intravenous infusion.

Amphotericin B (AmB) is widely used for the treatment of systemic mycoses. The current therapeutic regimens for this drug are complex and somewhat empirical, in part because of very limited information about the disposition kinetics of this agent. In this study, we examined the disposition kinetics of AmB as a function of dose and estimated clearance values using a steady state study design in an animal model. Groups of male Sprague-Dawley rats were given different two-step infusion regimens to achieve three different steady state concentrations (i.e., three different total infused doses). We observed no significant differences in systemic clearance among the three AmB doses studied. Similarly, only small differences were seen in volumes of distribution as a function of dose. However, renal clearance decreased significantly as the total infused dose was increased (0.76 +/- 0.33, 0.86 +/- 0.24, and 0.37 +/- 0.04 mL min-1 kg-1 for the low-medium and high-dose groups, respectively; p < 0.05). Signs of renal impairment were observed in the high-dose group, as documented by decreased creatinine clearance. Dose-dependent renal clearance may have been due either to nephrotoxicity associated with the high dose of AmB and/or to saturation of an active secretion process. Furthermore, clearance values estimated from steady state conditions were similar to those from time-averaged values (based on the estimation of area under the plasma concentration-time profile). This suggests that clearance calculations from time-averaged concentrations provide reasonable estimates, since steady state plasma concentrations could be reliably determined. However, the possibility that a true tissue steady state condition was not achieved with our study design cannot be ruled out. Further investigation is necessary to identify the renal excretion mechanisms of AmB and to reach steady state tissue concentration to confirm the estimation of systemic clearance.

Amphotericin B↗

Quantitative determination of cocaine, cocaethylene (ethylcocaine), and metabolites in plasma and urine by high-performance liquid chromatography.

A sensitive HPLC assay was developed to quantitate the relatively nonpolar compounds cocaine, cocaethylene (ethylcocaine), norcocaine, and norcocaethylene, as well as the relatively polar metabolites benzoylecgonine and benzoylnorecgonine, in rat plasma and urine. The assay in plasma employed two successive liquid-liquid extractions and separate injections onto two different columns (C8 and C18) to separate and quantitate the relatively polar and nonpolar compounds. In urine, the procedure employed a liquid-liquid extraction followed by solid-phase extraction (C18 light-load cartridges) and two separate injections as for plasma. The UV absorbance of the effluent was monitored at 235 nm. Linear standard curves were obtained over the concentration ranges of 25 to 1000 ng/mL and 5 to 250 ng/mL in plasma and urine, respectively. The inter- and intraday coefficients of variation for the assay of all compounds in plasma and urine were < 18% at low concentrations (12.5-100 ng/mL) and < 12% at high concentrations (125-250 ng/mL). There was no degradation of these compounds during the extraction procedure or during 2 months of storage at -20 degrees C. The quantitation limits for the assay of the relatively nonpolar and polar compounds in plasma were 25 (2.5 ng in 0.1 mL) and 50 ng/mL (5 ng in 0.1 mL), respectively. For the assay in urine, the quantitation limits were 5 (2.5 ng in 0.5 mL) and 12.5 ng/mL (6.25 ng in 0.5 mL) for the assay of the relatively nonpolar and polar compounds, respectively. The methods have been applied to quantitate those compounds in rat plasma.

Animals↗

Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide.

There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined. Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order). Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug. Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.

Amino Acid Sequence↗

Sensitive enantiomer-specific high-performance liquid chromatographic analysis of methamphetamine and amphetamine from serum using precolumn fluorescent derivatization.

In order to study the stereoselective disposition of methamphetamine (MAP), a widely abused drug, we have developed a sensitive HPLC assay to separate and quantitate the enantiomers of MAP and amphetamine (AP) in rat serum. Serum samples to which was added aniline sulfate (internal standard) were alkalized with 0.02 M carbonate buffer (pH 10.6) and extracted with ethyl acetate. Following back extraction with hydrochloric acid, neutralization, and reconstitution, the sample was derivatized with (-)-fluorenylethyl chloroformate overnight at room temperature. The derivatized products were separated following injection onto a reversed-phase C18 column. The mobile phase consisted of 0.02 M acetate buffer-acetonitrile-tetrahydrofuran (46:39:15, v/v). The fluorescent intensity of the effluent was monitored at excitation and emission wavelengths of 265 and 330 nm, respectively. The derivatized aniline, R-, S-AP, R- and S-MAP had retention times of 21.0, 22.6, 23.6, 27.7 and 29.0 min, respectively. Linear standard curves were obtained over the concentration range of 5-250 ng/ml. The inter-day and intra-day coefficients of variation for the assay of all four compounds at 12.5, 50.0 and 250 ng/ml were in the range of 2.1-18.6%. The method was applied to quantitate the concentrations of MAP and AP enantiomers in rat serum following a short term intravenous infusion of racemic MAP (15 mg/kg). There were no differences in serum concentrations of MAP enantiomers but the concentrations of S-AP were consistently greater than those of R-AP. These data suggest a stereoselective disposition for the formation and/or elimination of amphetamine.

Acetates↗

The effect of hepatic disease on the disposition of moricizine in humans.

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.

Administration, Oral↗

Pharmacokinetics of meso-2,3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults.

We compared the pharmacokinetics of meso-2,3-dimercaptosuccinic acid (DMSA) in three children with lead poisoning, three adults with lead poisoning, and five healthy adult volunteers. All subjects received DMSA orally. Maximum blood concentration and time to maximum blood concentration of total DMSA concentration were not statistically different among the groups. Unaltered DMSA was detected in the blood of all poisoned patients but in only one of five healthy volunteers. Elimination half-life of total DMSA (parent drug plus oxidized metabolites) was longer in children with lead poisoning (3.0 +/- 0.2 hours) than in adults with lead poisoning (1.9 +/- 0.4 hours) and healthy adults (2.0 +/- 0.2 hours). Renal clearance of total DMSA was greater in healthy adults (77.0 +/- 13.2 ml/min per square meter) than in either adults (24.7 +/- 3.3 ml/min per square meter) or children with lead poisoning (16.6 ml/min per square meter); renal clearance of the metabolites of DMSA was also greater in healthy adults (64.6 +/- 10.1 ml/min per square meter) than in either adults (35.4 +/- 8.4 ml/min per square meter) or children with lead poisoning (19.5 ml/min per square meter). The DMSA appeared to enter the erythrocytes of patients with lead poisoning to a greater extent than in healthy adults. We conclude that renal clearance of DMSA and its metabolites may be impaired and that the distribution of DMSA in children with lead poisoning may be different from that in adults.

Adult↗

Pharmacokinetics in the elderly.

Animals undergo substantial changes in many physiologic and biochemical functions as a natural consequence of aging. In the absence of disease or other pathologic conditions, these changes occur in a gradual manner with time (generally expressed as a fractional or percentage change in that function per year or decade). Furthermore, for any given function and at any given chronologic age, there is large variation in that function among individuals. Given the increase in life expectancy, the substantial increase in the number of elderly (and aged elderly) in the population, and the escalating costs of health care, there is great interest in learning more about the risks associated with aging as a result of toxic exposure. Are the elderly at greater risk than younger adults to the toxic effects of drugs and environmental exposure? Is the elderly population an inherently more sensitive one?

Aged↗

Determination and metabolism of dithiol chelating agents. XVI: Pharmacokinetics of 2,3-dimercapto-1-propanesulfonate after intravenous administration to human volunteers.

The pharmacokinetics of 2,3-dimercaptopropane-1-sulfonate (DMPS), an effective chelating agent for mercury, were determined in five healthy adults after i.v. administration of 3.0 mg/kg of DMPS. DMPS is rapidly transformed to disulfide forms; 15 min after administration, only 12% of the total DMPS detected in blood was present as the parent drug. DMPS and its metabolites were eliminated primarily by the kidneys. By 96 hr after administration, 12% of the total DMPS found in the urine was excreted as the parent drug (10% of the administered dose) and 88% was excreted as disulfide metabolites (74% of the administered dose). The disposition of parent drug was described by a biexponential equation with an elimination half-life of 1.8 hr. By contrast, the elimination half-life of total DMPS was 20 hr. The oral bioavailability of the parent drug was found in a separate study to be 39%. Mercury excretion in healthy volunteers correlated well with the urinary excretion of both the parent drug (r2 = .94) and the disulfide metabolites (r2 = .96).

Adult↗

Inhibitory effect of 4-methylpyrazole on antipyrine clearance in rats.

Pyrazole and 4-methylpyrazole (4-MP) are potent, effective inhibitors of alcohol dehydrogenase. Pyrazole and its derivatives also have been shown to affect the cytochrome P-450 dependent monooxygenase system. This study was performed to investigate the effect of 4-MP on the disposition kinetics of antipyrine (AP). Groups of male Fisher 344 rats were given an ip injection of 4-MP (100 mg/kg) or 4-MP HCl (equivalent to 4-MP 100 mg/kg) or an equivalent volume of saline. AP (20 mg/kg) was injected intravenously via the jugular vein catheter 30 minutes later. Blood samples were collected upto 24 hours and assayed by HPLC. 4-MP pretreatment significantly decreased AP clearance from 0.490 +/- 0.032 to 0.095 +/- 0.014 (4-MP HCl) and 0.076 +/- 0.008 (4-MP) L/hr.kg (p less than 0.01). The volume of distribution of AP decreased from 0.82 +/- 0.07 to 0.65 +/- 0.06 (4-MP HCl) and 0.56 +/- 0.04 (4-MP) L/kg (p less than 0.05). Mean residence time increased from 1.68 +/- 0.09 to 6.91 +/- 0.58 (4-MP HCl) and 7.39 +/- 0.56 (4-MP) hr (p less than 0.01). These results demonstrate a significant inhibitory effect of 4-MP on the cytochrome P-450 isozyme(s) which is responsible for AP metabolism in intact animals.

Animals↗

Effects of constriction bands on rattlesnake venom absorption: a pharmacokinetic study.

STUDY OBJECTIVE: To determine whether the use of a constriction band alters systemic absorption of rattlesnake venom in pigs and whether constriction band use alters local swelling. DESIGN: Using a crossover design, five pigs were studied with and without the use of a constriction band. 125I-Labeled Western Diamondback rattlesnake (Crotalus atrox) venom was injected subcutaneously into one foreleg. The protocol was repeated using the opposite foreleg six days later. The constriction band was applied at the time of injection and removed four hours later. Plasma radioactivity and leg circumference were measured serially. RESULTS: Maximum plasma venom concentration and area under the venom concentration-time curve were compared in trials with and without constriction band. Within the initial four hours, application of a constriction band decreased maximum plasma venom concentration by 25% and area under the venom concentration-time curve by 33% (P less than .05). After the constriction band removal at four hours, maximum plasma venom concentration and the area under the venom concentration-time curve were not significantly different between groups. Application of a constriction band did not result in a statistically significant increase in maximum leg circumference as compared with trials without a constriction band. CONCLUSION: The use of a constriction band was effective in reducing venom absorption while it was in place (reduced area under the venom concentration-time curve and maximum plasma venom concentration in the cuffed group), and constriction band removal did not result in a significant increase in maximum plasma venom concentration. Leg swelling was not affected by constriction band use. Because constriction band use delayed venom absorption without causing increased swelling, it may prove to be a useful first aid measure in human beings.

Absorption↗

Vitamin C bioavailability.

The above brief review indicates that the bioavailability of vitamin C in humans is complex and that our current understanding of that process and factors that influence it are incomplete. It is important that an overall pharmacokinetic scheme be developed and tested to completely describe the complex dispositional and absorption processes of the vitamin. Such information will provide a better understanding of the absorption and disposition of the vitamin per se. Furthermore, that information will permit us to better understand how those factors influence the participation of the vitamin in events associated with maintenance of health.

Administration, Oral↗