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Biomedical subjects

W A Colburn

Publications and source records attributed to W A Colburn.

At least 127 records · Page 7Linked to original sources
PubMed1975

Radioimmunoassay for cortisol using antibodies against prednisolone conjugated at the 3-position.

A radioimmunoassay for the measurement of cortisol in plasma was developed. The procedure requires a one-step precipitation of the proteins in plasma or a one-step extraction with methylene chloride in urine. The method is precise, accurate, sensitive, and very specific. The primary antibody was prepared against prednisolone-3- carboxymethoxime-bovine serum albumin. The method is sensitive to 12.5 pg/ml of plasma. The antiserum has little interference from other endogenous steroids and metabolites of cortisol. 0830 hour plasma levels of cortisol in twenty normal human adults averaged 150 +/- 33 ng/ml.

Adult↗
PubMed1975

In vitro effect of methylprednisolone on protein synthesis of activated canine thymus-derived lymphocytes.

Technics of studying the protein synthesis of canine thymus-derived lymphocytes in vitro have been developed. Activation of these cells by PHA or MLC increases protein synthesis. Methylprednisolone decreases the stimulation of protein synthesis of these activated lymphocytes. The decrease in protein synthesis is not caused by lympholysis. In this respect, the dog, like man, can be considered a steroid-resistant animal. It is postulated that this effect of methylprednisolone contributes to its immunosuppressive action by inhibiting the afferent limb of the immune response.

Animals↗
PubMedDate not supplied

Noncompartmental area under the curve determinations for drugs that cycle in the bile.

Drugs that are involved in the enterohepatic circulation (EHC) generally exhibit complex disposition profiles and are difficult to describe by classical methods. A noncompartmental method for calculating the area under the curve from time zero to time infinity (AUC) for substances that are involved the EHC is developed and tested. Previous methods have been based on specific compartmental models and/or have been limited to a single enterohepatic cycle. The current method uses the following equations: (formula; see text) for an IV dose or (formula; see text) for an oral dose where kaR is the apparent first-order absorption rate constant and beta R is the rate constant that describes the decline in blood concentrations of drug at 24-h intervals, i.e., 12, 36, and 60 or 24, 48, and 72 h, etc. AUC0-24 can be calculated by trapezoidal summation. The precision of this method is dependent on the number of observations during the 0-24 h sampling period as well as the accuracy of kaR and beta R. For drugs that are subject to a distinct distribution phase(s), error can be introduced into the AUC0-infinity value if pseudo-equilibrium has not been achieved during the first 24-hour interval. Although the method depends on a linearization process, it is truly concompartmental ('model-independent') in nature.

Animals↗
PubMedDate not supplied

Pharmacokinetics of 14C-etretinate in healthy volunteers and two patients with biliary T-tube drainage.

The pharmacokinetic profile of 14C-etretinate, a retinoid that is effective in the treatment of psoriasis, was studied in six healthy male volunteers and two biliary T-tube patients. Following a 100 mg oral dose of 14C-etretinate (20 microcurie), etretinate and its major blood metabolites (etretin, isoetretin) were measured by HPLC and total carbon-14 was measured in blood, bile, urine, and feces by liquid scintillation counting. Etretinate was extensively metabolized in healthy volunteers and in T-tube patients. During the absorption phase, 75 per cent of the total radioactivity in the blood could be accounted for as etretinate, etretin, and isoetretin whereas these compounds accounted for only approximately 12 per cent of the blood radioactivity in T-tube patients over the same time period. The blood concentrations of etretinate, etretin, and isoetretin appeared to be substantially reduced in T-tube patients compared to those in healthy volunteers. A higher proportion of the total drug was excreted in the feces and bile of the T-tube patients (84 per cent) than in the feces of healthy volunteers (62 per cent). The major factor responsible for the observed decrease in etretinate blood concentrations following biliary cannulation appears to be the reduced absorption of etretinate due to the elimination of solubilizing bile salts in the duodenum. Carbon-14 related material was detected in urine and feces for as long as 3 weeks in healthy subjects supporting the previous observation that a long terminal elimination half-life exists for etretinate, even following a single dose of the compound.

Bile↗
PubMedDate not supplied

Pharmacokinetics of isotretinoin following a single oral dose.

A pharmacokinetic profile was developed following oral administration of a single 100-mg oral dose of isotretinoin to 12 normal male volunteers. Concentrations of isotretinoin and its isomer, tretinoin, were measured in blood samples from 12 subjects and in urine and fecal samples from three of the 12 subjects. Blood concentration-time data during a 72-hour sampling interval were variable and, in five of the 12 cases, showed pronounced secondary and tertiary concentration maxima which were consistent with the theory of enterohepatic circulation (EHC) of isotretinoin in man. In five of the 12 subjects, adequate fits of the data could not be obtained using classical bi- or triexponential equations but were successfully fitted using a recently developed recycling model. Maximum blood concentrations of isotretinoin ranged from 74 to 511 ng/ml and occurred between 1 and 4 hours after dosing. Secondary maxima generally occurred between 6 and 24 hours after dosing. The harmonic mean elimination half-life was approximately 20 hours. These findings suggest that steady-state blood concentrations should be observed within one week. Negligible amounts of unchanged isotretinoin were excreted in urine, whereas 53 to 74 per cent of the dose was recovered as intact isotretinoin in the feces. The amount of intact drug in the feces could reflect biliary excretion of the conjugate of isotretinoin that is deconjugated beyond the site where absorption may occur, as well as unabsorbed drug.

Administration, Oral↗
PubMedDate not supplied

Food increases the bioavailability of isotretinoin.

Twenty healthy male subjects received 80 mg (2 X 40 mg SEG capsules) oral isotretinoin separated by two-week washout periods in an open randomized crossover design. Isotretinoin was administered during a complete fast, 1 hour after a standard breakfast, with a standard breakfast, or 1 hour before a standard breakfast. Blood samples were obtained at specific times over a 72-hour period. Isotretinoin blood concentrations were determined by a specific HPLC method. The relative bioavailability (AUC) of isotretinoin was found to be approximately 1.5 to 2 times greater when the dose was administered 1 hour before, concomitantly with, or 1 hour after a meal than when it was given during a complete fast. In addition, because the Cmax value is lower when the dose is administered with food rather than 1 hour after a meal, coadministration of isotretinoin with food may be the best method of administration.

Adult↗
PubMedDate not supplied

Effect of meals on the kinetics of etretinate.

Eight healthy men received 100 mg oral doses of etretinate separated by two-week washout periods in an open, randomized, crossover study. Etretinate was administered during a complete fast, with a standard high fat breakfast, a standard high carbohydrate breakfast, and 16 ounces of whole milk. Plasma samples were obtained at specific times over a 48-hour period. Plasma concentrations of etretinate as well as two of its major metabolites were determined by a specific, reverse-phase, high-performance liquid chromatography method. Plasma concentrations of etretinate were greater when administered with a high fat meal and whole milk compared to ingestion with a high carbohydrate meal or during a complete fast. In contrast, there was no increase in the plasma concentrations of the active metabolites following any of the meals. These data indicate that chronic dosing of etretinate with milk or a high fat meal compared with fasting conditions will result in higher concentrations of etretinate, which may ultimately lead to higher metabolite concentrations.

Adult↗
PubMedDate not supplied

Pharmacokinetic and pharmacodynamic modeling of cibenzoline plasma concentrations and antiarrhythmic effect.

The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total-data set, average-data set, and grouped-data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average-data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.

Adult↗
PubMedDate not supplied

Influence of food on the pharmacokinetics of quinapril and its active diacid metabolite, CI-928.

A randomized two-way crossover study was conducted in 12 healthy volunteers to assess the effect of food on the pharmacokinetics of quinapril (CI-906) and its active metabolite, CI-928, after quinapril dosing. Forty-milligram oral quinapril doses were administered in a fasted or a fed state with a one-week washout period between treatments. No significant treatment differences were observed in quinapril and CI-928 values for maximum plasma concentration, area under the plasma concentration-time curve, or percentage of dose excreted in the urine. Small but significant increases of less than 0.5 hour in quinapril and CI-928 tmax values were observed after consumption of food. The pharmacokinetic profiles of quinapril and CI-928 were not significantly altered by the administration of food.

Adult↗
PubMedDate not supplied

Clinical pharmacokinetics of the retinoids.

Etretinate, isotretinoin (13-cis-retinoic acid), and tretinoin (all-trans-retinoic acid) are retinoic acid analogues comprising a group of compounds known as the retinoids. However, they exhibit distinct and important differences with regard to their therapeutic and toxicological profiles. Tretinoin, due to a low oral therapeutic index, is limited almost exclusively to topical application, whereas etretinate and isotretinoin are therapeutically effective when given systemically by the oral route. Clinical doses of isotretinoin range from 0.5 to 8 mg/kg/day, with acute side effects appearing following doses of 1 mg/kg/day or greater. Plasma concentrations of isotretinoin following single and multiple doses peak between 2 to 4 hours and exhibit elimination half-lives of 10 to 20 hours. Isotretinoin blood concentration-time curves following a single- or multiple-dose regimen are well described by a linear model with biphasic disposition characteristics. Etretinate, which possesses a narrower therapeutic concentration range than isotretinoin, is used clinically at doses between 0.5 to 1.5 mg/kg/day; acute side effects appear following doses of 0.5 mg/kg/day or more. In most conditions, the retinoids produce a maximal effect in about 8 weeks (at the highest tolerated dose), with a slow recurrence of symptoms usually occurring within several weeks following cessation of treatment - except in the treatment of cystic acne with isotretinoin. Maintenance or intermittent dosing usually results in a prolongation of remission. Pharmacokinetically, the major difference between isotretinoin and etretinate is the much longer elimination half-life (120 days) of etretinate following long term administration. Recently, however, blood concentration versus time curves from day 1 to day 180 of etretinate therapy have been fitted by a single polyexponential pharmacokinetic equation without the need to invoke non-linearity in the kinetics. The observed lengthening of the elimination half-life with multiple dosing may thus be due to a lack of assay sensitivity at drug concentrations seen after single-dose administration, rather than to time-related alterations in the pharmacokinetics of etretinate.

Etretinate↗
PubMedDate not supplied

Pharmacokinetics of oral cibenzoline in arrhythmia patients.

The pharmacokinetics of oral cibenzoline were studied in 30 arrhythmia patients as part of an ascending multiple-dose efficacy study. The elimination half-life of the drug following repetitive dosing ranged from 7.6 to 22.3 hours, with a harmonic mean of 12.3 hours (n = 24), and increased with age and decreasing renal function. The drug exhibited apparent dose proportional and linear pharmacokinetics over the range of doses studied. Multivariate analysis revealed that the patients' age and serum creatinine concentration accounted for 71% of the variability in the range of beta values (terminal elimination rate constant), and that 69.5% of the intersubject variability in the steady-state trough plasma concentrations could be accounted for by the patients' age, weight and serum creatinine concentration. These data suggest that, although there is some intersubject variability in the elimination and accumulation of cibenzoline, much of the variability can be explained by the patients' age, weight and renal function.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetic model of presystemic metabolism.

A pharmacokinetic perfusion model is presented that describes the disposition of drugs that are subject to both first-pass hepatic and intestinal epithelial metabolism. Equations are developed to estimate hepatic and intestinal epithelial clearances by determining drug concentrations as a function of time in both portal and peripheral vein blood after oral and iv administration, and by determining or estimating the flow rate of blood perfusing the gastrointestinal tissues. A method that can be used, under the stated conditions, to approximate the systemic availability after oral administration of drugs subject to presystemic metabolism is also developed.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetics of 14C-isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage.

The pharmacokinetics of isotretinoin and 4-oxoisotretinoin in blood, as well as the blood concentrations and urinary, biliary, and fecal excretion of carbon-14 were studied using liquid scintillation counting techniques and reverse phase HPLC methods following a single 80-mg oral suspension dose of 14C-isotretinoin to four healthy male subjects and two patients with biliary T-tube drainage. Approximately 80% of the dose was recovered as 14C in excreta during the course of the study of which about equal fractions were in the urine and feces. Secondary peaks in blood concentrations of 14C were observed in the healthy subjects whereas they were not seen in the patients with T-tubes. The harmonic mean apparent half-life for isotretinoin in the blood of the healthy subjects was 13.6 hr, whereas the corresponding value for the 14C was 90 hr. Although a rigorous comparison of pharmacokinetic parameters between healthy subjects and T-tube patients was not feasible due to the limited number of subjects studied, comparisons of certain trends in the pharmacokinetic profiles gave some possible insights into the role of biliary excretion and enterohepatic cycling on the disposition of isotretinoin. The data for isotretinoin and 4-oxoisotretinoin coupled with the total carbon-14 data suggest that the oral dose of 14C-isotretinoin is absorbed to a similar extent by the healthy subjects and T-tube patients, whereas T-tube patients clear the drug more rapidly. The biliary excretion and possible enterohepatic circulation of isotretinoin and its metabolites may have significant impact on the pharmacokinetic profile of isotretinoin in man.

Adult↗