Twelve normal subjects each received single 300-, 600-, and 1200-mg oral doses of oxaprozin according to a three-period crossover design. Total drug plasma concentrations did not increase in proportion to the dose administered. Total clearance (CIo) and volume of distribution (Vd) increased with dose, though elimination t1 2 remained unchanged. The fraction of unbound oxaprozin in plasma (fup) varied linearly with total plasma concentration: it increased from 0.068 per cent at 10 micrograms/ml to 0.180 per cent at 170 micrograms/ml. A parameter fup was therefore introduced to express the average degree of unbound drug plasma for a given dose, and to allow the calculation of unbound volume of distribution (Vdu) and intrinsic clearance (CIi) as if binding were constant. Even though fup increased with dose, the overall binding in the body (fub approximately 0.52 per cent) was relatively stable. Neither Vdu nor CIi changed with dose; hence, unbound oxaprozin kinetics can be considered to be linear. Protein binding had no effect on unbound oxaprozin plasma levels within the given dose range, and there was a one-to-one proportionality between the dose administered and the unbound drug concentration in plasma.

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PubMedDate not supplied

Effects of food on oxaprozin bioavailability.

Twelve healthy volunteers received single 1200-mg oral doses of oxaprozin while fasting and immediately after a standard breakfast in a two-period crossover design with three weeks between administrations. Oxaprozin plasma concentrations were monitored during a 10-day period after each dose. No statistically significant differences were noted between kinetic parameters obtained in the fasting and post-prandial states for mean peak plasma concentrations (Cmax, 103 vs. 109 micrograms/ml), absorption rate constants (ka, 1.1 vs. 0.8 h-1), or total AUC (7042 vs. 7066 micrograms/ml X hr). Compared with doses administered during fasting, postprandial doses led to a delay in the onset of absorption in the gastrointestinal tract (lag time t0, 24 vs. 9 min), but not in the peak time (tmax approximately 5 hours). Oxaprozin's mean residence time t was slightly shorter for subjects in the postprandial state (72 hours) than for those in fasting state (73 hours), probably because of the intrasubject variability in half-life (48 vs. 50 hours). The results of this study indicate that the ingestion of food has no effect on the bioavailability of oxaprozin.

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PubMedDate not supplied

Pharmacokinetic disposition of guanabenz in the rhesus monkey.

The pharmacokinetics of guanabenz (E-2,6-dichlorobenzylidene aminoguanidine acetate, Wy-8678) in rhesus monkeys given 14C-labeled and unlabeled drug were investigated. The radioactive dose was well absorbed after intragastric (ig) administration of 1 mg of the labeled drug per kg, as indicated by tissue and urinary recovery of the label. Excretion into urine accounted for 57 +/- 3 (SE)% of the radioactive ig dose. Recovery of radioactivity in urine after iv administration of 0.2 mg/kg was 79 +/- 0.6% of the radioactive dose. Less than 1% of the dose was recovered in urine as unchanged drug after either route of administration. Plasma concentration/time profiles after 1-mg/kg iv and ig doses were fitted by polyexponential equations with a terminal elimination half-life of 12.0 +/- 1.1 hr. A large volume of distribution (VSSD = 10.3 +/- 0.7 liters/kg) indicated extensive extravascular distribution of the drug, which was confirmed by 14C-distribution studies. The systemic clearance was 27.5 +/- 1.4 ml/min/kg with hepatic clearance appearing to be the major determinant in guanabenz elimination. Dose proportionality was evident from a comparison of areas under the plasma concentration-time curves (AUC) of 1- and 5-mg/kg ig doses. The low systemic availability of 0.19-0.31 reflects the extensive presystemic extraction (first-pass effect) of the drug. Similarities in the pharmacokinetics of guanabenz in man and the rhesus monkey indicate that the latter species may serve as a satisfactory model for man in disposition studies.

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PubMedDate not supplied

Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics.

This single- and multiple-dose, nonrandomized, inpatient study was conducted to determine the effects of age and gender on the pharmacokinetic profiles of the antidepressant venlafaxine and its equally active metabolite, O-desmethylvenlafaxine. The subjects were 18 elderly (age 60-80 yrs) and 18 young (age 21-44 yrs) subjects, 9 men and 9 women per age group. They received a single 50-mg venlafaxine dose followed by 50-mg doses every 8 hours for 5 days. No significant differences in venlafaxine single-dose pharmacokinetics were seen between age groups, but the steady-state half-life increased 24% in the elderly. For O-desmethylvenlafaxine, single doses had a significantly lower apparent clearance in the elderly (0.29 vs 0.38 L/hr/kg), longer half-life (13.2 vs 10.3 hrs), and 14% greater steady-state half-life. For the composite (venlafaxine+O-desmethylvenlafaxine), there was a nonsignificant 16% increase in elderly steady-state area under the curve (AUC* = AUC+activity factor AUCm), and AUC* was linear between doses and age groups. We conclude that venlafaxine dosage adjustments for age or gender are not necessary based on pharmacokinetics.

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PubMedDate not supplied

Pharmacokinetic-pharmacodynamic relationships of bromfenac in mice and humans.

The relationship between pharmacodynamic effect and plasma concentrations of the analgesic bromfenac was assessed retrospectively. The drug was administered in single doses of 5, 10, 25, 50, or 100 mg to patients with oral surgery pain. Concentration-effect curves were generated by a semiparametric pharmacokinetic-pharmacodynamic procedure. The bromfenac EC50 (the effect site concentration giving 50% of the maximum effect) was estimated to be 0.36 microgram/ml in patients when all five dose groups were combined, and an Emax model was used for pharmacodynamic response. A similar EC50 value, 0.40 microgram/ml, was obtained when bromfenac was tested in a mouse pain model. On the basis of combined-dose data, effect site concentrations were predicted to be above the analgesic EC50 for approximately 7-8 hours after a 50-mg bromfenac dose was taken in the fasting state. Predictions based on a pharmacokinetic-pharmacodynamic modeling procedure were in reasonable agreement with the clinical observations.

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