von Moltke Ll

Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine : comparison with other selective serotonin reuptake inhibitor antidepressants

In vitro preparations of human liver microsomes were used to study the inhibiting effects of two selective serotonin reuptake inhibitor (SSRI) antidepressants, paroxetine and fluvoxamine, on metabolism via hydroxylation of alprazolam and of desipramine. These reactions are mediated by Cytochromes P450-3A4 and P450-2D6, respectively. Paroxetine was a highly potent inhibitor of desipramine hydroxylation; the inhibition constant (Ki) value of 2.0 microM indicated greater inhibiting potency than fluoxetine or norfluoxetine. The in vitro data predicted in vivo impairment of desipramine clearance by coadministration of paroxetine which was in the same range as observed in a clinical study. Fluvoxamine, by contrast, was a much weaker inhibitor of desipramine hydroxylation, having a Ki value (16.6 microM) similar to those of sertraline and desmethylsertraline. For hydroxylation of alprazolam, paroxetine was a relatively weak inhibitor, approximately comparable to fluoxetine, whereas fluvoxamine showed inhibiting capacity similar to that of norfluoxetine. The in vitro data predicted the degree of impairment of alprazolam clearance observed in vitro model can therefore provide clinically relevant data on prediction of potential drug interactions with SSRIs.

Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo.

Biotransformation of the H-1 antagonist terfenadine to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations of human liver. These metabolic reactions are presumed to be mediated by Cytochrome P450-3A isoforms. The azole antifungal agent ketoconazole was a highly potent inhibitor of both reactions, having mean inhibition constants (Ki) of 0.037 and 0.34 microM for desalkyl- and hydroxy-terfenadine formation, respectively. Itraconazole also was a potent inhibitor, with Ki values of 0.28 and 2.05 microM, respectively. Fluconazole, on the other hand, was a weak inhibitor. Six selective serotonin reuptake inhibitor antidepressants tested in this system were at least 20 times less potent inhibitors of terfenadine metabolism than was ketoconazole. An in vitro-in vivo scaling model used in vitro Ki values, typical clinically relevant plasma concentrations of inhibitors, and presumed liver:plasma partition ratios to predict the degree of terfenadine clearance impairment during coadministration of terfenadine with these inhibitors in humans. The model predicted a large and potentially hazardous impairment of terfenadine clearance by ketoconazole and, to a slightly lesser extent, by itraconazole. However, fluconazole and the six selective serotonin reuptake inhibitors (SSRIs) at usual clinical doses were not predicted to impair terfenadine clearance to a degree that would be of clinical importance. Caution is nonetheless warranted with the coadministration of SSRIs and terfenadine when high doses of SSRIs (particularly fluoxetine) are administered. Also, some individuals may be unusually susceptible to metabolic inhibition for a variety of reasons.

Differential impairment of triazolam and zolpidem clearance by ritonavir.

Background: The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450‐3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases. Methods: The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double‐blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low‐dose ritonavir (four doses of 200 mg), or with placebo. Results: Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4% of control values (p < .005), prolonged elimination half‐life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p < .08), and slightly prolonged elimination half‐life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. Conclusion: Short‐term low‐dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.

Human cytochromes and some newer antidepressants: kinetics, metabolism, and drug interactions.

The appearance of selective serotonin reuptake inhibitor antidepressants in the mid-1980s caused the discipline of clinical psychopharmacology to refocus attention to the topics of drug metabolism and drug interactions. This article reviews the metabolic profiles of some newer antidepressants, the clinical implications of metabolic properties, and research methodology that can be applied in determining which specific human cytochromes P450 (CYP) mediate metabolic pathways. Also reviewed are the relative activities of various new antidepressants as inhibitors of CYPs, and the benefits and drawbacks of in vivo and in vitro methodologies for identification and quantitation of drug interactions.

Kinetics and dynamics of lorazepam during and after continuous intravenous infusion

ObjectiveTo evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. MethodsNine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 &mgr;g/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. ResultsThe bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. ConclusionDespite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.

EXTRAPOLATING IN VITRO DATA ON DRUG METABOLISM TO IN VIVO PHARMACOKINETICS: EVALUATION OF THE PHARMACOKINETIC INTERACTION BETWEEN AMITRIPTYLINE AND FLUOXETINE

Recently, models have been proposed to extrapolate in vitro data on the influence of inhibitors on drug metabolism to in vivo decrement in drug clearance. Many factors influence drug clearance such as age, gender, habits, diet, environment, liver disease, heredity, and other drugs. In vitro investigation of hepatic cytochrome P450 activity has generally centered on genetic influences and interactions with other drugs. This group of enzymes is involved in many, although not all, drug interactions. The interaction of amitriptyline and fluoxetine is an example. Of the different in vitro paradigms, interaction studies utilizing human liver microsomal preparations have proved to be the most generally applicable for in vitro scaling models. Assuming Michaelis-Menten conditions and applying nonlinear regression, a hybrid inhibition constant (Ki) can be generated that allows classification of the inhibitory potency of an inhibitor toward a specific reaction. This constant is largely independent of the substrate concentration, but in vivo relevance is critically dependent on the inhibitor concentration in the site of metabolic activity, the liver cell cytosol. Many lipophilic drugs are extensively bound to plasma protein but, nonetheless, demonstrate extensive partitioning into liver tissue. This is not compatible with diffusion only of the unbound drug fraction into liver cells. The introduction of a partition factor, based on data from a number of possible sources, provided a reasonable basis for the scaling of in vitro data to in vivo conditions. Many interactions could be reconstructed or predicted with greater accuracy and clinical relevance for interactions such as terfenadine or midazolam and ketoconazole. Even for less marked interactions such as amitriptyline and fluoxetine, this model provides a forecast consistent with the clinically observed range of 22-45% reduction in oral clearance, although this interaction is complicated by the presence of two inhibitors, fluoxetine and norfluoxetine. The concept of in vitro-in vivo scaling is promising and might ultimately yield a fast and more cost-effective screening for drug interactions with reduced human drug exposure and risk.

Appetite suppressant drugs as inhibitors of human cytochromes P450: in vitro inhibition of P450-2D6 by D- and L-fenfluramine, but not phentermine.

The activity of D-fenfluramine, L-fenfluramine, and phentermine as inhibitors of five human cytochromes P450 was evaluated using human liver microsomes in vitro. All three compounds produced negligible inhibition of P450-1A2, -2C9, -2E1, and -3A. Phentermine also did not inhibit P450-2D6. However, D- and L-fenfluramine significantly inhibited P450-2D6 activity as measured by dextromethorphan O-demethylation, with mean 50% inhibitory concentrations (15.1 microM) within one order of magnitude of that for fluoxetine (2.7 microM). Findings from the in vitro assay are consistent with clinical studies showing significant inhibition of desipramine clearance by coadministration of fenfluramine.