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Biomedical subjects

W A Colburn

Publications and source records attributed to W A Colburn.

At least 73 records · Page 4Linked to original sources
PubMed1984

Pharmacokinetic analysis of concentration-time data obtained following administration of drugs that are recycled in the bile.

A pharmacokinetic model for calculating the pharmacokinetic parameters for a compound that is recycled in the bile is presented and tested using theoretical as well as experimental data. The results indicate that this method is stable and only slightly susceptible to sampling and recycling times. It is apparent from the present study that pharmacokinetic terms that have been used in classical situations are not directly applicable to drugs that enter the enterohepatic circulation. Effective half-life and effective clearance are used to describe the intrinsic ability of the eliminating organs to remove drug from the blood, whereas net half-life and net clearance are used to describe the irreversible elimination of the drug from the body.

Bile↗
PubMed1984

Pharmacokinetics of diazepam and nordiazepam in the cat.

The cat has been used extensively as an experimental model for studying the pharmacology of compounds that exhibit CNS activity including diazepam and nordiazepam. However, since little is known about the distribution and elimination of diazepam in this species, the pharmacokinetics of diazepam and nordiazepam were studied in the cat following intravenous doses of 5, 10, and 20 mg/kg of diazepam and 5 and 10 mg/kg of nordiazepam. The disappearance of diazepam and nordiazepam from blood was fitted with classical equations. Theoretical and trapezoidal areas under the curve (AUCth and AUCtr) were calculated. The volumes of distribution (Vd beta) were calculated as model-independent parameters for diazepam and nordiazepam. Intrinsic hepatic clearance, extraction ratio, and tissue binding parameters were also calculated for diazepam. From the observed data, it is apparent that the blood concentrations and the resulting areas under the curves are proportional to the dose of diazepam administered and that the pharmacokinetics of diazepam were linear over the dose range studied. In addition, nordiazepam formed after diazepam administration appeared to be proportional to the dose of diazepam administered. The terminal elimination rate constant of nordiazepam remained constant over the dose range studied. It appears that both diazepam and nordiazepam are highly bound to tissue. The total body clearance of diazepam (4.72 +/- 2.45 mL/min/kg) is approximately six times that of nordiazepam (0.85 +/- 0.25 mL/min/kg). Approximately 50% of an administered dose of diazepam was biotransformed to nordiazepam in the cat.

Animals↗
PubMed1984

Pharmacokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal subjects.

The pharmacokinetics of bumetanide was studied in 12 normal subjects after 1-mg intravenous, intramuscular, oral solution, and tablet administrations in a random four-treatment crossover design. Plasma and urine concentrations of intact bumetanide were analyzed by a sensitive and specific RIA. The pharmacokinetics of bumetanide after intravenous administration was characterized by a biexponential equation, including an initial disposition phase (t 1/2, alpha = 5.1 min), followed by a slower elimination phase (t 1/2, beta = 44 min). Bumetanide pharmacokinetics after intramuscular and oral administration could be described by a biexponential equation with first-order absorption and elimination. Bumetanide is rapidly absorbed via the intramuscular and oral routes, with mean +/- SD maximum plasma concentrations of 38.2 +/- 9.8 (intramuscular), 34.0 +/- 10.6 (oral solution), and 30.9 +/- 14.6 ng/mL (tablet) achieved within 0.34 +/- 0.23, 0.76 +/- 0.27, and 1.8 +/- 1.2 h after dosing, respectively. The drug is rapidly eliminated from the body after intravenous, intramuscular, oral solution, and oral tablet administrations, with half-lives ranging from 24-86, 47-139, 27-71, and 26-99 min, respectively. Approximately 70% of a parenteral dose and 60% of an oral dose are excreted as intact drug in urine taken 0-24 h after administration. The extent of bioavailability of bumetanide from the tablet and oral solution dosage forms are equivalent, and the absolute bioavailability of the intramuscular and oral preparations are approximately 100 and 80%, respectively. This is consistent with the predicted limited extent of first-pass metabolism after complete absorption of an oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1983

Pharmacokinetic model for diazepam and its major metabolite desmethyldiazepam following diazepam administration.

A five-compartment open model was used to simulate the blood concentration profiles of diazepam and its metabolite, desmethyldiazepam, following single- and multiple-dose administrations of diazepam. The parameter estimates for diazepam were previously reported literature values. The parameters estimates for the metabolite were calculated from literature values of blood concentrations of desmethyldiazepam following the administration of clorazepate. The five-compartment open model suggests that approximately 50% of the administered diazepam is biotransformed to desmethyldiazepam, and that the elimination profile of the metabolite is not altered by the presence of the drug. The model may also be readily adapted to predict the concentrations of diazepam and desmethyldiazepam in cerebrospinal fluid following the administration of diazepam by simply correcting the blood or plasma concentrations of the drug and metabolite for the degree of plasma protein binding.

Adult↗
PubMed1983

Pharmacokinetics of isotretinoin and its major blood metabolite following a single oral dose to man.

A pharmacokinetic profile of isotretinoin and its major dermatologically active blood metabolite, 4-oxo-isotretinoin, was developed following a single 80 mg oral suspension dose of isotretinoin to 15 normal male subjects. Blood samples were assayed for isotretinoin and 4-oxo-isotretinoin using a newly developed reverse-phase HPLC method. Following rapid absorption from the suspension formulation, isotretinoin is distributed and eliminated with harmonic mean half-lives of 1.3 and 17.4 h, respectively. Maximum concentrations of isotretinoin in blood were observed at 1 to 4 h after dosing. Maximum concentrations of the major blood metabolite of isotretinoin, 4-oxo-isotretinoin, are approximately one-half those of isotretinoin and occur at 6 to 16 h after isotretinoin dosing. The ratio of areas under the curve for metabolite and parent drug following the single dose suggests that average steady-state ratios of metabolite to parent drug during a dosing interval will be approximately 2.5. Both isotretinoin and its metabolite can be adequately described using a single linear pharmacokinetic model.

Administration, Oral↗
PubMed1983

Pharmacokinetics of isotretinoin during repetitive dosing to patients.

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.

Adult↗
PubMed1983

A time-dependent volume of distribution term used to describe linear concentration-time profiles.

The present study was conducted to develop, test, and apply a single exponential time-dependent volume of distribution function to describe the pharmacokinetics of compounds following instantaneous, zero-order and first order input. Simulations were used to show the applicability and flexibility of the equations. Experimental data from the literature were fitted using the equations developed in the present study. In addition, the results of these fitted curves were compared to the results of the original fitting procedures to compare and contrast the methods. In the present analysis, the change from an initial volume (V1) to the total volume (V T) is perceived as a simple exponential function. Therefore, a single exponential term to describe elimination and a single exponential term to describe the change from V1 to V T were used to describe the entire blood concentration profile. The results from present simulations and fitted data indicate that the transition from V1 to V T is a more continuous process than observed with classical methods and is consistent with results obtained from physiologic flow-limited models. This observation suggests that the present curve-fitting technique may be more akin to physiologic reality, in that it depicts the change from the initial volume of distribution to the total volume of distribution as a continuous exponential function which reflects the establishment of an equilibrium.

Ampicillin↗
PubMed1983

A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines.

Ex vivo receptor binding as a function of time was determined in Charles River rats. The pharmacokinetic and protein binding parameters in man as well as the ex vivo receptor binding parameters in rat brain for three benzodiazepine induction agents, diazepam, lorazepam and midazolam, were used to develop and test a pharmacokinetic/pharmacodynamic/receptor binding model. The model was subsequently used to predict changes in receptor binding and pharmacodynamics as a function of changes in pharmacokinetics. The model was found to be a good predictor of the relative onset and duration of the sedative and amnesic properties in normal subjects as well as in the presence of certain patho-physiological conditions and certain drug interactions.

Animals↗
PubMed1983

Multiple-dose pharmacokinetics of diazepam following once-daily administration of a controlled-release capsule.

The study was designed to determine the steady-state pharmacokinetic profile of diazepam and desmethyldiazepam following a 15-mg controlled-release capsule dosed once daily at either 7 a.m. or 11 p.m. compared with the respective profiles of the conventional 5-mg tablet dosed three times a day at 7 a.m., 12 p.m., and 5 p.m. Plasma concentrations of diazepam and desmethyldiazepam were assayed by an electron-capture gas-liquid chromatographic method. Plasma concentrations indicated that there were no differences between the pharmacokinetic profiles following the 7 a.m. or 11 p.m. dosings of the controlled-release capsule. Steady-state concentrations of diazepam were attained between days 7 and 9 during the controlled-release dosing, and the accumulation profiles are similar to those observed for the conventional tablet given three times a day. Nearly identical areas under the diazepam plasma concentration-time curves (AUC) on day 1 and at steady state for both regimens indicate equal extents of absorption from the two formulations. In addition, the steady-state AUCs for desmethyldiazepam were independent of formulation. The data indicate that a single daily dose of the 15-mg controlled-release capsule results in accumulation and steady-state profiles comparable to those observed following a regimen of the 5-mg conventional tablet three times a day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Pharmacokinetics of a single intramuscular injection of vitamin E to premature neonates.

The pharmacokinetics of parenterally administered vitamin E (d, l-alpha tocopherol) in serum were developed using data from five premature neonates (1,500 +/- 100 gm) receiving a single 20 mg/kg intramuscular injection. Blood samples were obtained immediately prior to drug administration to establish baseline vitamin E concentrations: then further sampling was performed at various intervals for up to 7 days. It was assumed that dietary intake of vitamin E did not markedly alter serum concentration of vitamin E during the 7-day study and that the total intramuscular dose was absorbed. Although extensive sampling could not be performed in any one neonate, composite sampling from the study population made it possible to construct a pharmacokinetic profile of vitamin E in premature neonates. The half-life of elimination was 44 hours, the volume of distribution (V beta) was 0.41 liter/kg. and serum clearance was 6.5 ml/hr/kg. Vitamin E is an important biological antioxidant that may provide protection to the retinas and lungs of premature infants exposed to supplemental inspiratory oxygen. Therefore, if the pharmacokinetics of vitamin E observed in the present study can be generalized to the population of premature infants, a single 10 mg/kg intramuscular (IM) loading dose followed by 5 mg/kg every 48-72 hours should maintain serum concentration of 1.5 to 2.5 mg%--a level that has been associated with antioxidant protection.

Female↗
PubMed1983

Gentamicin-specific antiserum alters the disposition of gentamicin by the isolated perfused rat kidney.

Previous studies have indicated that antibodies or Fab fragments of antibodies can be used to alter the pharmacologic or toxicologic effects of drugs. The present study was conducted to determine the effect of specific antiserum administration on the renal excretion of a drug with a high nephrotoxic potential (e.g., gentamicin) using the IPK. After a perfusion period during which the renal clearance of gentamicin was determined, either serum or gentamicin-specific antiserum was added to the perfusion medium. Experiments with serum addition served as controls for a comparison of the effects of antiserum addition on gentamicin renal clearance and tissue accumulation. Addition of antiserum decreased the renal clearance and tissue accumulation of gentamicin. Increasing perfusate gentamicin concentrations at the end of the experimental time suggested that these alterations in disposition could be due to the formation of a nonfilterable gentamicin-antiserum complex. The addition of antiserum also rapidly reversed the increasing fractional excretion of potassium ion. Therefore it would appear that a commercially available antiserum is capable of decreasing renal tissue accumulation of gentamicin and that the IPK represents a viable system for studying the effects of antisera on renal drug disposition.

Animals↗
PubMed1982

Pharmacokinetics of the retinoids isotretinoin and etretinate. A comparative review.

The clinical pharmacokinetic profiles of two orally administered retinoids, isotretinoin and etretinate, are discussed and compared. The pharmacokinetic profile of isotretinoin is predictable and can be described using linear pharmacokinetic theory. The drug is rapidly absorbed following oral administration, is highly bound to plasma protein, and is metabolized to 4-oxo-isotretinoin. The apparent half-lives of elimination of isotretinoin and 4-oxo-isotretinoin following the oral administration of isotretinoin range from 10 to 20 hours and 24 to 29 hours, respectively. Steady-state pharmacokinetic profiles in patients are consistent with the single-dose pharmacokinetics in normal subjects. Following oral administration, etretinate undergoes significant first-pass biodegradation to its corresponding carboxylic acid; the acid appears rapidly in the circulation, often earlier than the parent drug, and its plasma concentration is usually comparable to, or greater than, that of the parent drug. The apparent elimination rates of drug and metabolite are similar (6-13 hours) following a single dose, suggesting that metabolite elimination may be formation-rate limited. During multiple dosing of etretinate, a very slow terminal elimination phase is observed which is not detected after single-dose administration. The prolonged half-life of this phase suggests accumulation in a deep tissue compartment. Differences between the two retinoids reflect their differing physicochemical properties.

Acne Vulgaris↗