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W R Gillespie

Publications and source records attributed to W R Gillespie.

At least 37 records · Page 2Linked to original sources
PubMed1987

Theorems and implications of a model-independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. IV. Exact relationship between the terminal log-linear slope parameter beta and drug clearance.

An exact formula relating the terminal log-linear beta parameter and the drug clearance is derived. The expression is valid for drugs with a linear, polyexponential disposition kinetics. The formula is useful for calculating the clearance when the clearance has changed between drug administrations and requires only drug level data from the terminal, log-linear elimination phase in addition to data from a single separate i.v. administration in the same subject. Data from an i.v. administration are necessary in order to apply the disposition decomposition technique to isolate and uniquely define the distribution kinetics in terms of the distribution function h(t). The different clearances can then be calculated from the beta values of the log-linear terminal drug level data and the parameters of h(t). The theoretical basis of the method and its assumptions and limitations are discussed and various pertinent theorems are presented. A computer program enabling an easy implementation of the proposed method is also presented. The mathematical and computational procedures of the method are demonstrated using kinetic data from i.v. and oral administrations of cimetidine, diazepam, and pentobarbital in human subjects. The classical V.beta method of approximating the clearance as the product of volume of distribution and beta is considered for comparison. For the three drugs considered the V.beta method which assumes a single exponential disposition kinetics leads to excessive errors when applied in absolute clearance comparisons. However, when applied in relative comparisons in the form of the "beta correction" the errors cancel out to some extent depending on the magnitude of the distribution kinetic effect. Whenever possible it is advisable to apply the proposed method to avoid such errors.

Cimetidine↗
PubMed1986

Ibuprofen kinetics in plasma and synovial fluid of arthritic patients.

After administration of a single dose and at steady state, ibuprofen concentrations were measured simultaneously in plasma and synovial fluid obtained from eight patients with rheumatoid arthritis. By seven hours after a dose at steady state, the mean synovial fluid: plasma ibuprofen concentration ratios were constant, and the synovial fluid levels were, on average, greater than those in plasma. The extent to which ibuprofen was bound to protein was somewhat greater in plasma than in synovial fluid. As a result, the mean synovial fluid:plasma free concentration ratio for seven-hour and later specimens was greater than that based on total concentrations. The degree of accumulation of ibuprofen in each fluid was minimal, consistent with its short half-life.

Adult↗
PubMed1986

Single pass mean residence time in peripheral tissues: a distribution parameter intrinsic to the tissue affinity of a drug.

The single pass mean residence time in peripheral tissues, tp1, is a characteristic constant of linear pharmacokinetic systems and nonlinear systems with linear distribution kinetics. It is descriptive of distribution kinetics in such systems and is not dependent on elimination kinetics as are other related parameters, e.g., mean residence time in peripheral tissues, tp. Equations are derived which permit estimation of tp1 from experimental data for systems in which no peripheral elimination occurs. The type of data required are systemic drug levels resulting from iv administration. The probability density function for single pass residence time in peripheral tissues is derived. It is shown that tp1 is related to the amount of drug in the peripheral tissues at steady state according to (Ap)ss = CLdCsstp1, where CLd is the distribution clearance, and Css is the steady-state systemic drug level. Values of tp1 are presented for several drugs.

Humans↗
PubMed1986

A note on appropriate constraints on the initial input response when applying deconvolution.

When deconvolution is employed to estimate cumulative input profiles, nonzero initial values may result unless certain constraints are imposed on the function used to approximate the input response c(t). It is shown that the initial value of the response to a nonimpulse input is zero, i.e., c(t0) = 0, where t0 is the input lag time. If, in addition, the initial value of the impulse response is zero, i.e., c delta (0) = 0, then c'(t0) = 0. Therefore, it is appropriate to impose the constraint c(t0) = 0 in general and c'(t0) = 0 when c delta (0) = 0 if c(t) is the response to a nonimpulse input. The use of such constraints is demonstrated in an example where the cumulative in vivo dissolution profile is estimated by deconvolution.

Animals↗
PubMed1986

Linear systems approach to the analysis of an induced drug removal process. Phenobarbital removal by oral activated charcoal.

The theory of linear systems analysis is applied to the evaluation of induced drug removal processes. The rate and extent of removal are determined by deconvolution for the case of phenobarbital removal from the systemic circulation by orally administered activated charcoal. The proposed method is model independent in the sense that no specific models of intrinsic or induced pharmacokinetic processes are required, and it is readily adapted to the analysis of most types of induced removal processes (hemodialysis, peritoneal dialysis, etc.). Application of the approach indicates that phenobarbital was removed from the systemic circulation to an extent of 25-53% following multiple oral doses of activated charcoal in healthy human subjects.

Charcoal↗
PubMed1985

Deconvolution applied to the kinetics of extracorporal drug removal. Haemodialysis of cefsulodin.

A novel approach to the evaluation of the kinetics of drug removal by an extracorporal device (ECD), e.g., haemodialysis, haemofiltration, and haemoperfusion, is presented. The rate and extent of extracorporal drug removal (ECR) are determined by deconvolution. The proposed method is model independent in the sense that no specific models of corporal or extracorporal disposition are required. The estimation of various derived functions and parameters useful for describing ECR such as clearance and fractional drug removal are facilitated by the technique. The kinetics of cefsulodin elimination by haemodialysis in 3 patients were evaluated using the deconvolution approach. The results indicated that cefsulodin was dialyzable with approximately 50% of the drug in the body removed by haemodialysis over 3-4 h.

Cefsulodin↗
PubMed1985

The determination of mean residence time using statistical moments: it is correct.

The present communication seeks to end a controversy created by a recent publication regarding the applicability of statistical moment principles for determination of mean residence time of drug in the body tb. It is shown that the equation tb = AUMC/AUC is correct when applied to pharmacokinetic systems in which the total drug elimination rate is directly proportional to the drug concentration in the systemic circulation, i.e., first-order central elimination. More general equations for tb in terms of elimination rate, amount eliminated, and amount in the body are presented along with demonstrations of their utility.

Body Burden↗
PubMed1985

Theorems and implications of a model-independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions. II. Clearance concepts applied to the evaluation of distribution kinetics.

The disposition decomposition approach is employed to derive clearance parameters descriptive of drug distribution kinetics. The name distribution clearance, CLd, is given to a characteristic constant of linear and some nonlinear pharmacokinetic systems. CLd is the clearance associated with the steady-state rate of drug transfer from the peripheral tissues to the systemic circulation. Also introduced is the elimination clearance, CLe, which is associated with the total drug transfer rate from the systemic circulation in linear systems. Estimates of CLd and CLe are presented for several drugs.

Animals↗
PubMed1985

A polyexponential deconvolution method. Evaluation of the "gastrointestinal bioavailability" and mean in vivo dissolution time of some ibuprofen dosage forms.

A new deconvolution algorithm (DCON) suitable for pharmacokinetic applications is presented. It requires that both the impulse and input responses, typically systemic drug levels, be well described by polyexponential equations. DCON has a wider range of applications than an earlier method (DECONV) from which it is derived. A FORTRAN program is provided, making implementation of the technique a simple matter. DCON is demonstrated to evaluate the "GI bioavailability," defined as the rate and the extent of gastrointestinal drug release, of various ibuprofen dosage forms. The GI drug release kinetics exemplifies a pharmacokinetic system which cannot be evaluated using the previous deconvolution algorithm (DECONV) because of an initial zero drug level response. This limitation is not found in DCON. It is also demonstrated how the mean in vivo dissolution time MDT can be evaluated by deconvolution.

Biological Availability↗
PubMed1984

Effects of age on the clinical pharmacokinetics of ibuprofen.

The pharmacokinetics of ibuprofen (Motrin) were studied in 17 normal elderly men and women aged 65 to 78 years. Total and free unbound plasma concentrations of ibuprofen were determined 12 hours after single oral doses of 400, 800, and 1,200 mg. These results were then compared with those of a similar study involving 15 normal young men 22 to 35 years old. The two age groups showed no statistically significant differences in any pharmacokinetic parameter studied. Therefore, according to this study, advanced age has only minimal influence on the pharmacokinetics of ibuprofen, and dosage apparently does not need to be adjusted for age.

Adult↗
PubMed1984

Excretion of ibuprofen into breast milk.

Concentrations of ibuprofen in breast milk and serum were compared in 12 patients who had ingested one 400 mg tablet of ibuprofen every 6 hours over a 24-hour period for relief of post-cesarean section pain. Samples of breast milk and blood were obtained simultaneously over a 34-hour period beginning just prior to the first dose of ibuprofen. Gas-liquid chromatography assay methodology capable of detecting 1 microgram/ml was used to determine concentrations of ibuprofen in serum and breast milk. Ibuprofen was present in the serum with a half-life of approximately 1.5 hours. No measurable amounts of ibuprofen were found in the samples of breast milk. The conclusion drawn is that, in lactating women who take up to 400 mg of ibuprofen every 6 hours, less than 1 mg of ibuprofen per day is excreted in breast milk.

Adult↗
PubMed1984

Determination of ibuprofen in capillary and venous plasma by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic (HPLC) method is described which determines ibuprofen in human capillary or venous plasma. Ibuprofen plus the internal standard, flurbiprofen, were extracted from acidified plasma with pentane-ether, back-extracted into base, and then extracted into the pentane-ether solution after acidification of the aqueous phase. A reverse-phase octadecylsilane column with acetonitrile-water-phosphoric acid as mobile phase and UV detection provided a quantifiable peak for 1 microgram/mL of ibuprofen in 0.1 mL of plasma. Capillary and venous plasma level curves were virtually superimposable after administration of 400 mg of ibuprofen to four normal volunteers. No ibuprofen was detected in the saliva of the subjects.

Capillaries↗
PubMed1984

Determination of flurbiprofen in human serum by reverse-phase high-performance liquid chromatography with fluorescence detection.

A reverse-phase high-performance liquid chromatographic method is described for the determination of flurbiprofen in human serum. Flurbiprofen is extracted from hydrochloric acid-acidified serum with pentane-ether (80:20). An octadecylsilane column was used with a mobile phase of acetonitrile-water-phosphoric acid (650:350:0.5, v/v/v). A fluorescence detector with excitation at 250 nm and emission at 315 nm provided a quantifiable peak for 0.1 microgram/mL of flurbiprofen in 0.5 mL of plasma. A comparison between UV and fluorescence detection systems is presented. The method is applicable to human bioavailability and pharmacokinetic studies with flurbiprofen.

Chromatography, High Pressure Liquid↗
PubMed1983

Influence of route of administration on the pharmacokinetics of methylprednisolone.

This study was conducted to evaluate the influence of route of administration upon the bioavailability and pharmacokinetics of methylprednisolone sodium succinate. Fourteen healthy adult male volunteers received 40 mg doses of methylprednisolone as the following treatments after an overnight fast in a 4-way crossover design: (a) as a 1 ml i.v. bolus; (b) as a 1 ml i.m. injection; (c) administered as an oral solution; and (d) as 5 X 8 mg oral tablets. Both the ester and free methylprednisolone were determined in plasma and urine. Study results indicate that the ester is rapidly and extensively converted to free methylprednisolone after all routes. The extent of methylprednisolone absorption was equivalent after i.v. and i.m. administration. Both orally administered treatments resulted in a lower extent of absorption attributed to a first-pass effect. Although a slightly lower extent of absorption was demonstrated following the oral administration of the methylprednisolone sodium succinate solution relative to the methylprednisolone oral tablets, this average difference of 9% would probably be of minimal therapeutic importance.

Absorption↗
PubMed1983

Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships.

Ibuprofen kinetics were studied in 15 subjects after four oral doses. Plasma levels of both total and free ibuprofen were measured for 12 hr, and urine was collected for 48 hr after the doses. All subjects showed a nonlinear relationship between dose and total ibuprofen plasma AUC. Free ibuprofen plasma AUC, however, was linearly related to the dose, suggesting that oral clearance based on free drug was dose independent. Urinary recovery data indicated that efficiency of absorption was dose independent.

Administration, Oral↗
PubMed1983

Ibuprofen and acetaminophen kinetics when taken concurrently.

We evaluated kinetics of ibuprofen and acetaminophen taken concurrently by 20 healthy adults in a randomized crossover design. Steady-state blood levels of ibuprofen and acetaminophen were measured by gas-liquid chromatography and HPLC. There were no significant differences in any of the ibuprofen serum concentrations, but there were differences in acetaminophen serum concentrations in 5 of 19 sampling times. When bioavailability and kinetic parameters for both drugs were compared, there were no significant differences. Our data demonstrate that steady-state kinetics of ibuprofen and acetaminophen are not changed when taken concurrently.

Absorption↗
PubMed1983

The bioavailability of an orally administered medroxyprogesterone acetate suspension.

The relative bioavailability of an orally administered aqueous suspension of medroxyprogesterone acetate (MPA) intended for intramuscular injection (Depo-Provera) was determined in relation to orally administered tablets. Serum levels of MPA were determined by radioimmunoassay following the administration of 400-mg doses to 19 adult male volunteers in a crossover design after an overnight fast. The two treatments were judged bioequivalent based upon a comparison of the resultant MPA serum levels and the derived bioavailability parameters. Hence, the intramuscular suspension administered orally offers an alternative means of achieving optimal serum levels of MPA in patients requiring high dose therapy.

Administration, Oral↗