Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers.

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.

Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan, a CYP2D6 probe.

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7, 28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2-fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine.

Effect of venlafaxine on CYP1A2-dependent pharmacokinetics and metabolism of caffeine.

Venlafaxine is a clinically effective antidepressant. Caffeine is a metabolic probe for the quantitative measurement of CYP1A2 activity in vivo. This open-label study evaluated the effect of steady-state venlafaxine on CYP1A2-dependent metabolism, as measured by the pharmacokinetic disposition of caffeine, and urinary caffeine metabolite ratios (CMRs). Sixteen healthy subjects received 200 mg of caffeine orally before (Day 1) and after (Day 8) venlafaxine was titrated to steady-state (37.5 mg every 12 hours on Days 2-4, then 75 mg every 12 hours on Days 5-8). Samples were collected before and for 24 hours after caffeine dosing for the determination of caffeine in plasma and 1,7-dimethylxanthine, 3,7-dimethylxanthine, 1,7-dimethyluric acid (17U), 1-methylxanthine (1X) and 1-methyluric acid (1U), and 5-acetylamino-6-amino-3-methyluracil (AAMU) in urine. Blood samples were obtained before venlafaxine doses on Days 7 and 8 (morning dose only) for the determination of trough venlafaxine and O-desmethylvenlafaxine levels. Venlafaxine did not significantly alter the pharmacokinetics of caffeine and its metabolites. Plasma caffeine AUC was unchanged and remained within the bioequivalence criteria (90% confidence interval: 87.9%-102%) in the presence of venlafaxine. Urine metabolite data showed variable increases and decreases in the CMR [(AAMU + 1U + 1X)/17U] for individual subjects. However, the mean CMR was altered by < 10% in the presence of venlafaxine. This in vivo study demonstrated that venlafaxine did not alter the pharmacokinetic profile of caffeine and confirms in vitro data that venlafaxine does not inhibit CYP1A2 metabolism. Therefore, venlafaxine appears to have a relatively low potential for drug interactions based on CYP1A2 inhibition.

Effect of venlafaxine on the pharmacokinetics of risperidone.

An open-label study evaluated the effect of steady-state venlafaxine on the single-dose pharmacokinetic profile of risperidone, a CYP2D6 substrate; its active metabolite, 9-hydroxyrisperidone; and the total active moiety (risperidone plus 9-hydroxyrisperidone). Thirty healthy subjects received a 1 mg oral dose of risperidone before and after venlafaxine dosing to steady state. No significant changes occurred between treatments in the area under the concentration-time curve (AUC) for 9-hydroxyrisperidone or the total active moiety. However, venlafaxine weakly altered the pharmacokinetics of risperidone. Oral clearance decreased 38%, and the volume of distribution decreased 17%, resulting in a 32% increase in the AUC for risperidone. Renal clearance of 9-hydroxyrisperidone also decreased by 20% in the presence of venlafaxine. Safety profiles of both drugs were not altered. This study demonstrated that venlafaxine did not affect the pharmacokinetic profile of 9-hydroxyrisperidone or the total active moiety, although it weakly inhibited the metabolism of risperidone. These results show that venlafaxine is unlikely to be involved in a pharmacokinetic interaction with concomitant risperidone.

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam.

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

Kinetics of drug action in disease states. XXI. Relationship between drug infusion rate and dose required to produce a pharmacologic effect.

Computer simulations were performed to determine if the threshold dose of an infused drug (rather than the drug concentration in the biophase at onset of action) can be a suitable index for pharmacodynamic investigations as proposed by others. A two-compartment pharmacokinetic model with drug elimination from the central compartment was used for the simulations. Drug was administered into the central compartment by a constant-rate infusion, and concentrations in the central and peripheral compartments were calculated as a function of time. The pharmacologic effect was assumed to be reversible and to occur at a defined concentration (the effective concentration) in one or the other compartment. The dose required to produce an effective concentration (threshold dose) was determined as a function of infusion rate. The relationship between infusion rate and the dose required to produce an effective concentration in the peripheral compartment was found to be affected by drug distribution and elimination kinetics and by the effective concentration. The infusion rate-dose relationship showed a dose minimum at an infusion rate which others have designated as the "optimal dose rate" and have used for pharmacodynamic studies. No such minimum occurred for pharmacologic effects associated directly with drug concentrations in the central compartment. Since optimum dose rate and threshold dose are affected by both pharmacokinetic and pharmacodynamic alterations, it is concluded that this method (which avoids determination of drug concentrations) is not generally suitable for quantitative pharmacodynamic investigations.

Simultaneous determination of tacrine and 1-hydroxy-, 2-hydroxy-, and 4-hydroxytacrine in human plasma by high-performance liquid chromatography with fluorescence detection.

An analytical method was developed for the simultaneous reversed-phase (cyano) high-performance liquid chromatographic determination with fluorescence detection of tacrine and 1-hydroxy-, 2-hydroxy-, and 4-hydroxytacrine in human plasma. Alkalinized human plasma samples were extracted with a mixture of chloroform/l-propanol (90:10, v/v). Extraction recoveries generally ranged from 68% to 83% for all four compounds and did not appear to be concentration dependent over the range examined. Calibration curves were constructed over the following ranges: 0.5-30.0 ng/mL for tacrine (THA) and 4-hydroxytacrine (4-OH-THA), 1.0-30.0 ng/mL for 2-hydroxytacrine (2-OH-THA), and 0.925-46.2 ng/mL for 1-hydroxytacrine (1-OH-THA). The intra- and interassay precision (RSD) for the quality control specimens analyzed during validation were < or = 11.8% and < or = 9.28%, respectively. The intra- and interassay accuracy (RE) for the quality control specimens analyzed during validation ranged from 14.1% to -7.5% and 12.1% to -3.33%, respectively, for all four compounds. The limit of quantitation was estimated as the level of the lowest concentration in the calibration curve for each compound based on acceptable interassay precision and accuracy statistics generated at this concentration. The sensitivity of the method was adequate for the determination of THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA following oral administration of Cognex (40 mg single dose) to normal volunteers.

Kinetics of drug action in disease states. XXV. Effect of experimental hypovolemia on the pharmacodynamics and pharmacokinetics of desmethyldiazepam.

It has been reported that hypovolemia secondary to extensive blood loss alters the functionality of the central nervous system and is associated with changes in the dose requirements or intensity of action of various central nervous system depressants, including a benzodiazepine. To investigate the mechanism(s) of this effect, the influence of experimental hypovolemia on the pharmacodynamics, receptor binding and pharmacokinetics of a benzodiazepine drug was determined. Adult male Sprague-Dawley rats were made hypovolemic by removal of about 30% of their blood over 30 min. An i.v. infusion of desmethyldiazepam (DDZP) was started 30 min later and continued until the animals lost their righting reflex. Compared to results obtained with normal controls, the hypovolemic rats required about one-half the dose of DDZP to produce loss of righting reflex and had significantly lower DDZP concentrations in serum and cerebrospinal fluid at that time. This effect of substantial blood removal could not be reversed by prompt return of the removed blood to the animals. Experimental hypovolemia had no apparent effect on the in vitro binding of tritiated diazepam to benzodiazepine receptor sites in the cerebral cortex of rats. The plasma clearance of DDZP was decreased significantly and the biological half-life was increased in hypovolemic rats compared to normal animals when both received a 30-mg/kg dose by i.v. infusion over 10 min. It is concluded that acute hemorrhagic hypovolemia increases the sensitivity of the central nervous system to the depressant effect of DDZP and decreases the body clearance of that drug in rats. Thus, the pharmacodynamics as well as the pharmacokinetics of a benzodiazepine are altered by hypovolemia.

Kinetics of drug action in disease states. XXIV. Pharmacodynamics of diazepam and its active metabolites in rats.

The purpose of this investigation was to determine the relative contribution of diazepam and its active metabolites (desmethyldiazepam, oxazepam and temazepam) to the hypnotic activity of this benzodiazepine drug and to assess the role of rate of drug administration as a determinant of the relative concentrations of diazepam and its active metabolites in serum and in the central nervous system at the onset of a predefined pharmacologic endpoint. Rats were given i.v. infusions of diazepam to onset of loss of righting reflex. Samples of cerebrospinal fluid (CSF), blood (for serum) and brain were obtained at that time and were analyzed for diazepam and its active metabolites. Based on the results of six experiments on groups of 6 to 14 rats performed at the same time of day over 11 months, the pharmacologic response of the animals was found to be relatively consistent, with little variation between rats and between experiments in body weight-normalized effective dose and in diazepam serum and CSF concentrations. All three active metabolites of diazepam were found in serum, CSF and brain; they were relatively more prominent in CSF than in serum. Variation of the diazepam infusion rate (four rates between 0.10 and 0.34 mg/min per approximately 200-g rat) was associated with changes in average onset time (50 to 10 min) and dose (26 to 17 mg/kg) required to produce the pharmacologic effect. The drug and metabolite concentrations in CSF determined in these experiments, together with corresponding concentrations obtained by infusion of each active metabolite individually, yielded estimates of their relative hypnotic potency that were unaffected by differences in serum protein binding and tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of drug action in disease states. XXXI. Effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine (oxazepam) in rats.

This investigation was designed to determine the effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine and on the binding characteristics of the benzodiazepine receptor complex. Rats were made hyperthyroid by subcutaneous implantation of slow release pellets containing L-thyroxine. This treatment produced the characteristic symptoms of hyperthyroidism: increased serum thyroxine concentrations, increased heart weight and body temperature, and decreased serum protein concentrations. The hyperthyroid rats and a parallel group of normal animals (with drug-free pellets implanted subcutaneously) were slowly infused intravenously with oxazepam until they lost their righting reflex. The hyperthyroid rats required a significantly larger dose of the benzodiazepine and their total serum and cerebrospinal fluid concentrations of oxazepam (but not the serum concentration of free drug and the brain concentration) at the onset of loss of the righting reflex were modestly but statistically significantly lower than those of the normal rats. The receptor density and affinity for diazepam in hyperthyroid rats were not significantly different from those of the normal animals. Hyperthyroidism apparently affects the pharmacokinetics of oxazepam but has, at best, only a small effect on the pharmacodynamics (hypnotic activity) of the drug.

Effect of venlafaxine on the pharmacokinetics of alprazolam.

Potential pharmacokinetic effects of venlafaxine on alprazolam, a substrate of the cytochrome pigment 450 (CYP) isoenzyme CYP3A4, were investigated in 16 healthy volunteers. A single 2-mg oral dose of alprazolam was combined with steady-state levels of venlafaxine administered orally at 75 mg twice daily. The levels of alprazolam in plasma and of alprazolam, alpha-hydroxyalprazolam, and 4-hydroxyalprazolam in urine were determined. Steady-state venlafaxine and O-desmethylvenlafaxine concentrations in plasma were reached before venlafaxine was coadministered with alprazolam. Coadministering venlafaxine increased the apparent oral clearance and volume of distribution of alprazolam by 36 percent and 9 percent, respectively, and decreased the alprazolam area under the concentration-time curve and half-life by 29 percent and 21 percent, respectively. There were small but statistically significant increases in mean baseline scores for the digit-symbol substitution and symbol copying tests, probably reflecting a time-dependent learning effect. The maximum score decrease from baseline for these two tests also increased, possibly representing an additive effect of alprazolam and venlafaxine. Overall, venlafaxine did not inhibit the CYP3A4-mediated metabolism of alprazolam in vivo, which corroborates other in vitro and in vivo data showing a lack of CYP3A4 inhibition with venlafaxine.

Effect of venlafaxine on the pharmacokinetics of terfenadine.

The effect of steady-state venlafaxine administration on the single-dose pharmacokinetic profile of terfenadine, a cytochrome pigment (P450) isoenzyme CYP3A4 substrate, and its active acid metabolite (fexofenadine) was evaluated in an open-label, nonrandomized study. Twenty-six healthy subjects were given a 120-mg oral dose of terfenadine before and after venlafaxine was titrated up to steady-state. Blood samples were drawn before terfenadine dosing and at various intervals for 48 hours after dosing to measure plasma concentrations of terfenadine and its acid metabolite. Blood samples were obtained before each venlafaxine dose to measure trough levels of venlafaxine and O-desmethyl-venlafaxine. Single-dose pharmacokinetic parameters of terfenadine did not change significantly in the presence of steady-state venlafaxine. However, terfenadine acid metabolite area under the plasma concentration-time curve decreased by approximately 25 percent; this was not thought to be related to the P450 isoenzyme system. These results are consistent with in vitro studies and in vivo studies with other CYP3A4 substrates, indicating that venlafaxine has a low potential for drug-drug interactions that result from inhibition of the CYP3A4 isoenzyme.