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Biomedical subjects

P R Audet

Publications and source records attributed to P R Audet.

13 recordsLinked to original sources
PubMed1996

Pharmacokinetics and absolute bioavailability of epristeride in healthy male subjects.

The objective of the current investigation was to describe the pharmacokinetics and absolute oral bioavailability of epristeride. Twelve healthy male subjects (mean (SD) age, 27 (6.2) years) received a single oral dose of 5 mg and an intravenous infusion of 4.5 mg over 30 min in a crossover fashion. Blood samples were obtained over 72h for the determination of epristeride plasma concentrations using a sensitive high-performance liquid chromatography assay. The lower limit of quantification was 5 ng mL-1. Pharmacokinetic analysis of the plasma concentration-time data was performed by both non-compartmental and compartmental methods. Absolute bioavailability was determined using dose-normalized AUC values following oral and intravenous administration. Epristeride plasma concentrations declined in a biexponential fashion with secondary peaks evident around 24 h in a majority of subjects following both routes of administration. Maximal plasma concentrations were typically achieved approximately 4 h after oral dosing. The mean apparent terminal elimination half-life estimates were similar following intravenous and oral administration and were 27.3 and 26.2 h, respectively. The mean plasma clearance and steady-state volume of distribution were 0.33 (0.09) mL min-1 kg-1 and 0.54 (0.17) L kg-1, respectively. The mean absolute bioavailability was 93% (95% CI: 84%, 104%). Following compartmental analysis of the intravenous data, the mean (SD) lambda 1 and lambda 2 half-life estimates were 2.74 (0.48) and 31.8 (19.5) h, respectively. The % AUC associated with the lambda 2 exponential phase was approximately 68%. This long half-life allows for once-daily dosing of epristeride.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1996

Pharmacokinetics of testosterone in hypogonadal men after transdermal delivery: influence of dose.

To assess the pharmacokinetics of testosterone after application of one, two, or three testosterone transdermal delivery systems to hypogonadal patients, 12 hypogonadal men (mean age 46.6 +/- 10.5 years) were enrolled in an open-label, randomized, crossover study. Each application period comprised 4 days: a 2-day washout period with no exogenous testosterone therapy followed by 2 days of therapy with one, two, or three transdermal systems applied daily to the patient's back. On day 4 of each period, serial blood samples were collected for determination of total and non-sex hormone binding globulin (non-SHBG) bound serum testosterone concentrations. Serum concentrations of testosterone were determined using validated radioimmunoassay methods. Residual testosterone analysis of used transdermal systems was used to estimate testosterone delivery through the skin. In general, serum concentrations of testosterone rose in accordance with an increase in dose. Using a strict bioequivalence approach to dose proportionality, the increases in area under the concentration-time curve (AUC) and morning concentrations were proportional to the increase in dose from two to three transdermal systems, but somewhat less than proportional with an increase from one to two transdermal systems. Results from the non-SHBG bound serum testosterone concentrations closely paralleled those of total serum testosterone. Use of three transdermal systems yielded serum concentrations of testosterone that tended to be above the upper limit of the normal range. The AUC and cumulative release of testosterone were linearly related to the number of applied systems. If necessary, the standard recommended dose of two testosterone transdermal delivery systems can be modified to accommodate interindividual differences in testosterone requirements of hypogonadal men.

Administration, Cutaneous↗
PubMed1994

Comparative effects of nabumetone, sulindac, and indomethacin on urinary prostaglandin excretion and platelet function in volunteers.

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side-effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21-43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period-balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6-keto-PGF1 alpha, PGF2 alpha, thromboxane [TX] B2) and platelet function (collagen-induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2 alpha, but 6-keto-PGF1 alpha and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6-keto-PGF1 alpha and TXB2 excretion rates. Reduced excretion of PGF2 alpha was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6-keto-PGF1 alpha excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2 alpha excretion and between the NAB and SUL regimens for PGE2, PGF2 alpha, 6-keto-PGF alpha 1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6-keto-PGF1 alpha, suggests that NAB possesses renal sparing properties.

Adult↗
PubMed1994

Pharmacokinetics of famciclovir in subjects with chronic hepatic disease.

The pharmacokinetic profile of penciclovir was determined after a single 500-mg dose of its oral precursor, famciclovir, in 9 healthy volunteers and in 14 patients with chronic hepatic disease. Plasma and urine samples were analyzed for concentrations of penciclovir and 6-deoxy-penciclovir using a reverse-phase high-performance liquid chromatography (HPLC) method. Famciclovir was not quantifiable in patients with hepatic disease, and 6-deoxy-penciclovir was quantifiable in only a limited number of specimens. The extent of systemic availability of penciclovir, as measured by AUC0-infinity, was similar in patients with hepatic disease and in healthy subjects. In contrast, Cmax was significantly lower (average decrease of 43%) in subjects with hepatic disease relative to healthy normal subjects. Median Tmax for subjects with hepatic disease was significantly increased (by 0.75 hours) compared with subjects with normal liver function. These data suggest a decrease in the rate, but not the extent, of systemic availability of penciclovir in patients with hepatic disease. It should be unnecessary to modify the dose of famciclovir for subjects with compensated hepatic disease and normal renal function.

2-Aminopurine↗
PubMed1994

Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment.

OBJECTIVE: To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment. METHODS: Twenty-seven subjects were enrolled in an open-label parallel-group study. Eighteen patients had renal impairment (average age [ +/- SD], 49 +/- 12 years), and nine subjects were healthy volunteers (average age, 28 +/- 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CLCR): mild impairment (CLCR, 60 to 80 ml/min/1.73 m2), moderate impairment (CLCR, 30 to 59 ml/min/1.73 m2) and severe impairment (CLCR, 5 to 29 ml/min/1.73 m2). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reverse-phase HPLC. Plasma data were analyzed with use of model-independent methods. RESULTS: In subjects with normal renal function (CLCR > 80), the mean maximum plasma concentrations of penciclovir was 2.83 micrograms/ml (range, 1.30 to 3.82 micrograms/ml) and the mean time to reach maximum concentration was 0.89 hours (range, 1/2 to 1 1/2 hours). The mean apparent terminal elimination half-life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CLCR and between renal clearance and CLCR. Mean area under the plasma concentration-time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function. CONCLUSION: Consideration should be given to modification of the dosing schedule of famciclovir from the usual 8-hour interval to a 12-hour interval for patients with moderate renal impairment (CLCR 30 to 59 ml/min/1.73 m2) or a 24-hour interval for patients with severe renal impairment (CLCR < 30 ml/min/1.73 m2).

2-Aminopurine↗
PubMed1990

Lack of probenecid effect on nonrenal excretion of ceftriaxone in anephric patients.

Probenecid has been shown to decrease renal and biliary excretion of organic acids. In a randomized crossover study, the effect of coadministered probenecid on nonrenal excretion of ceftriaxone was studied in six functionally anephric patients in whom ceftriaxone is eliminated exclusively by nonrenal or presumably by biliary excretion. Each patient received 0.5 g IV ceftriaxone without and with probenecid (0.5 g at 10 and 2 hours prior to ceftriaxone and 0.5 g q12h X 3 doses post ceftriaxone). Serial blood samples were collected over 48 hours and plasma analyzed for ceftriaxone by high performance liquid chromatography (HPLC). Pharmacokinetic analysis was based on a model-independent approach. Probenecid did not significantly affect the disposition of ceftriaxone in this study, thus suggesting that nonrenal excretion of ceftriaxone is not inhibited by probenecid.

Adult↗
PubMed1988

Effect of renal impairment on disposition of pentopril and its active metabolite.

Disposition of pentopril was studied in 15 male volunteers with varying renal functions. Mild to moderate compromise in renal function did not demonstrate any appreciable changes in plasma concentration of pentopril, the prodrug ester of the active angiotensin-converting enzyme (ACE) inhibitor CGS 13934. This is consistent with the known elimination pattern for pentopril, which is eliminated primarily by hydrolysis to the active inhibitor. In contrast, the plasma concentration of the active ACE inhibitor was sensitive to moderate changes in renal function. Because of the reciprocal relationship of AUC and clearance, AUC did not change to any appreciable extent until creatinine clearance (CLCR) dropped to about 50 ml/min. Below 50 ml/min of CLCR, AUC and half-life increased sharply with reduced kidney function. Because of the significant contribution of the renal secretion process to total renal elimination of both pentopril and the active metabolite, prediction of renal clearance from CLCR was poor at relatively normal kidney function (CLCR greater than 80 ml/min). However, renal secretory clearances for both pentopril and metabolite were well correlated to p-aminohippuric acid clearance. In patients with moderately compromised renal function (glomerular filtration rate less than 40 ml/min), tubular secretion rate of creatinine approaches its glomerular filtration rate and hence CLCR could be used as a predictor of renal clearance and other disposition parameters. Plasma ACE activity also demonstrated prolonged inhibition with decreased renal function. Based on the prolonged blockade of plasma ACE activity, some correction in dose or dosing interval is anticipated in patients with moderately compromised renal function (CLCR less than 50 ml/min).

Adult↗
PubMed1988

Effect of chronic renal failure on oxaprozin multiple-dose pharmacokinetics.

The effects of renal disease on the steady-state kinetics of oxaprozin were assessed in eight patients on hemodialysis with normal serum albumin levels and eight normal subjects who received six doses. A larger clearance and volume of distribution at steady state for total and unbound oxaprozin occurred in the patients on hemodialysis. The elimination half-lives were not different. The mean total AUC, peak concentration, average steady-state plasma concentration, and trough concentration for total and unbound oxaprozin were decreased in the patients on hemodialysis. These differences are consistent with impaired absorption of oxaprozin in patients on hemodialysis. The higher dose-averaged unbound fraction of oxaprozin in plasma in patients on hemodialysis may be caused by endogenous binding inhibitors. Because clearance was not reduced in patients on hemodialysis, the dose of oxaprozin may not need to be reduced when albumin levels are normal.

Administration, Oral↗
PubMedDate not supplied

The effect of food on ciramadol bioavailability in normal subjects.

Eleven healthy volunteers completed a study to compare the relative bioavailability to orally administered ciramadol in a fasting versus postprandial state. A single oral dose of 30 mg of ciramadol was administered on two separate occasions, 2 weeks apart, in a randomized crossover study. A mono- or biexponential pharmacokinetic equation with first-order absorption was applied to analyse the serum data for each subject. Significant differences were found in peak time (tmax) and absorption time (tabs) whereas the mean AUCs for the two modes of administration were not significantly different. The relative bioavailability (F) of the drug when administered in the postprandial state with respect to the fasting state was 96 per cent. It is thus concluded that ingestion of food has no effect on the extent of absorption of ciramadol; however, food may alter its rate of absorption.

Adult↗
PubMedDate not supplied

Resin hemoperfusion for chloramphenicol intoxication.

A case report of a three kilogram, four month infant who received excessive doses of chloramphenicol for the treatment of bacterial meningitis is presented. The child was treated with resin hemoperfusion (XAD-4) to reduce her serum chloramphenicol concentration. Her treatment was complicated by hypocalcemia and thrombocytopenia. During hemoperfusion a mean clearance of chloramphenicol of 27.4 ml/min was achieved. This represents a significant improvement over normal body clearance (4.7 ml/min/kg) in pediatric patients. We conclude that using hemoperfusion is an effective modality which may be used as an adjunct to supportive therapy when there is a need to increase the body clearance of chloramphenicol.

Chloramphenicol↗