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1.
Eur J Clin Pharmacol ; 56(3): 259-61, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10952482

ABSTRACT

OBJECTIVE: Biotransformation of triazolam to its alpha-hydroxy and 4-hydroxy metabolites by human liver microsomes in vitro was used as an index of human cytochrome P450 3A (CYP3A) activity. RESULTS: The reaction was strongly inhibited by co-incubation with the viral protease inhibitors ritonavir (IC50 = 0.14 microM) and amprenavir (IC50 = 2.5 2.9 microM), and by the azole derivative ketoconazole (IC50 = 0.07 microM). Pre-incubation of microsomes with ritonavir or amprenavir increased inhibitory potency (IC50 reduced to 0.07 microM and 1.4 microM, respectively). This was not the case with ketoconazole. CONCLUSIONS: Thus, ritonavir and amprenavir are highly potent mechanism-based inhibitors of human CYP3A isoforms.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacology , Ketoconazole/pharmacology , Oxidoreductases, N-Demethylating/antagonists & inhibitors , Ritonavir/pharmacology , Sulfonamides/pharmacology , Carbamates , Cytochrome P-450 CYP3A , Furans , Humans , Hydroxylation , Triazolam/metabolism
2.
J Acquir Immune Defic Syndr ; 24(2): 129-36, 2000 Jun 01.
Article in English | MEDLINE | ID: mdl-10935688

ABSTRACT

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.


Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Aryl Hydrocarbon Hydroxylases , HIV Protease Inhibitors/pharmacology , Hypnotics and Sedatives/pharmacokinetics , Pyridines/pharmacokinetics , Ritonavir/pharmacology , Triazolam/pharmacokinetics , Adult , Anti-Anxiety Agents/blood , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Double-Blind Method , HIV Seronegativity , Half-Life , Humans , Hypnotics and Sedatives/blood , Male , Metabolic Clearance Rate/drug effects , Oxidoreductases, N-Demethylating/antagonists & inhibitors , Pyridines/blood , Triazolam/blood , Zolpidem
3.
Clin Pharmacol Ther ; 67(4): 335-41, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10801241

ABSTRACT

BACKGROUND: Pharmacokinetic interactions involving antiretroviral therapies may critically influence the efficacy and toxicity of these drugs, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor ritonavir is of particular concern since it both inhibits and induces the activity of cytochrome P450 3A (CYP3A) isoforms. METHODS: The inhibitory effect of ritonavir on the metabolism of alprazolam, a CYP3A-mediated reaction in humans, was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer subjects received 1.0 mg of alprazolam concurrent with low-dose ritonavir (four doses of 200 mg) or with placebo. RESULTS: Ritonavir was a potent in vitro inhibitor of alprazolam hydroxylation. The 50% inhibitory concentration was 0.11 micromol/L (0.08 microg/mL); this is below the usual therapeutic plasma concentration range (generally exceeding 2 microg/mL). In the clinical study, ritonavir reduced alprazolam clearance to 41% of control values (P < .001), prolonged elimination half-life (mean values, 30 versus 13 hours; P < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. CONCLUSION: Consistent with in vitro results, administration of low doses of ritonavir for a short duration of time resulted in large impairment of alprazolam clearance and enhancement of clinical effects. Removal from product labeling of a warning against coadministration of ritonavir and alprazolam was based on a previous study only of extended exposure to ritonavir, in which CYP3A induction offset inhibition. Kinetic interactions involving antiretroviral therapies may be complex and time dependent. Product labeling should reflect this complexity.


Subject(s)
Alprazolam/metabolism , Anti-Anxiety Agents/metabolism , Aryl Hydrocarbon Hydroxylases , HIV Protease Inhibitors/pharmacology , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Ritonavir/pharmacology , Adult , Alprazolam/blood , Alprazolam/pharmacokinetics , Anti-Anxiety Agents/blood , Anti-Anxiety Agents/pharmacokinetics , Antifungal Agents/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Double-Blind Method , Drug Interactions , Drug Labeling , Female , HIV Protease Inhibitors/blood , Humans , Hydroxylation/drug effects , Ketoconazole/pharmacology , Male , Metabolic Clearance Rate , Oxidoreductases, N-Demethylating/drug effects , Protein Isoforms/drug effects , Ritonavir/blood
4.
J Pharmacol Exp Ther ; 293(2): 435-43, 2000 May.
Article in English | MEDLINE | ID: mdl-10773013

ABSTRACT

Eighteen healthy volunteers (10 men and 8 women) participated in a single-dose, double-blind, three-way crossover pharmacokinetic and pharmacodynamic study. Treatment conditions were 0.25 mg of triazolam, a full-agonist benzodiazepine ligand; 10 mg of zolpidem, an imidazopyridine having relative selectivity for the type 1 benzodiazepine receptor subtype; and placebo. Weight-normalized clearance of triazolam was higher in women than in men (8.7 versus 5. 5 ml/min/kg), but the difference was not significant. In contrast, zolpidem clearance was lower in women than in men (3.5 versus 6.7 ml/min/kg, P <.06). Compared to placebo, both active medications produced significant benzodiazepine agonist-like pharmacodynamic effects: sedation, impaired psychomotor performance, impaired information recall, and increased electroencephalographic beta-amplitude. Effects of triazolam and zolpidem in general were comparable and less than 8 h in duration. There was no evidence of a substantial or consistent sex difference in pharmacodynamic effects or in the kinetic-dynamic relationship, although subtle differences could not be ruled out due to low statistical power. The complete dependence of triazolam clearance on CYP3A activity, as opposed to the mixed CYP participation in zolpidem clearance, may explain the differing sex effects on clearance of the two compounds.


Subject(s)
GABA Agonists/pharmacology , GABA Agonists/pharmacokinetics , GABA Modulators/pharmacology , GABA Modulators/pharmacokinetics , GABA-A Receptor Agonists , Pyridines/pharmacology , Pyridines/pharmacokinetics , Triazolam/pharmacology , Triazolam/pharmacokinetics , Adult , Affect/drug effects , Area Under Curve , Chromatography, Gas , Cross-Over Studies , Double-Blind Method , Electroencephalography/drug effects , Female , Half-Life , Humans , Hypnotics and Sedatives/pharmacology , Male , Middle Aged , Psychomotor Performance/drug effects , Sex Characteristics , Zolpidem
5.
Biopharm Drug Dispos ; 20(1): 49-52, 1999 Jan.
Article in English | MEDLINE | ID: mdl-10086837

ABSTRACT

To evaluate methodology for in vivo interaction studies of benzodiazepines (BZs) and ketoconazole (KCZ) in animal models, this study assessed the pharmacokinetics and electroencephalographic (EEG) effect of KCZ, and suitable dosage regimens of KCZ to maintain sufficiently high KCZ concentrations to inhibit metabolism of BZs in rats. Rats were injected intraperitoneally (i.p.) with KCZ 10 mg kg(-2). No significant EEG change was detected regardless of serum KCZ concentration, indicating that the EEG changes after both BZ and KCZ administration can be attributed entirely to BZ. Serum KCZ concentrations showed an apparent nonlinear pattern of decline with a short half-life (1.38 h). An additional dose of 5 mg kg(-1) i.p. given 180 min after the initial dose sustained KCZ concentrations above 2 pg mL(-1) until at least 500 min after the initial dose. These results provide the basis for design of animal models for in vivo assessment of interactions of BZs and KCZ.


Subject(s)
Anti-Anxiety Agents/antagonists & inhibitors , Antifungal Agents/pharmacokinetics , Electroencephalography/drug effects , Ketoconazole/pharmacokinetics , Animals , Anti-Anxiety Agents/metabolism , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Biological Availability , Chromatography, High Pressure Liquid , Half-Life , Injections, Intraperitoneal , Ketoconazole/administration & dosage , Ketoconazole/pharmacology , Male , Metabolic Clearance Rate , Midazolam/antagonists & inhibitors , Midazolam/metabolism , Rats , Rats, Sprague-Dawley
6.
Clin Pharmacol Ther ; 64(3): 278-85, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9757151

ABSTRACT

BACKGROUND: Macrolide antimicrobial agents may impair hepatic clearance of drugs metabolized by cytochrome P4503A isoforms. Potential interactions of triazolam, a substrate metabolized almost entirely by cytochrome P4503A in humans, with 3 commonly prescribed macrolides were identified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled clinical study. METHODS: In an in vitro model using human liver microsomes, 250 mumol/L triazolam was incubated with ascending concentrations (0 to 250 mumol/L of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo. RESULTS: Mean 50% inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 mumol/L troleandomycin, 27.3 mumol/L erythromycin, 25.2 mumol/L clarithromycin, and greater than 250 mumol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. CONCLUSION: The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.


Subject(s)
Anti-Bacterial Agents/pharmacology , Aryl Hydrocarbon Hydroxylases , Cytochrome P-450 Enzyme System/drug effects , Hypnotics and Sedatives/pharmacokinetics , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Oxidoreductases, N-Demethylating/drug effects , Triazolam/pharmacokinetics , Administration, Oral , Azithromycin/pharmacology , Clarithromycin/pharmacology , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Double-Blind Method , Erythromycin/pharmacology , Humans , Hypnotics and Sedatives/metabolism , In Vitro Techniques , Microsomes, Liver/enzymology , Oxidoreductases, N-Demethylating/metabolism , Time Factors , Triazolam/metabolism , Troleandomycin/pharmacology
7.
Clin Pharmacol Ther ; 64(6): 661-71, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9871431

ABSTRACT

BACKGROUND: Azole antifungal agents may impair hepatic clearance of drugs metabolized by cytochrome P450-3A isoforms. The imidazopyridine hypnotic agent zolpidem is metabolized in humans in part by P450-3A, as well as by a number of other cytochromes. Potential interactions of zolpidem with 3 commonly prescribed azole derivatives were evaluated in a controlled clinical study. METHODS: In a randomized, double-blind, 5-way, crossover, clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received (A) zolpidem placebo plus azole placebo, (B) 5 mg zolpidem plus azole placebo (C) zolpidem plus ketoconazole, (D) zolpidem plus itraconazole, and (E) zolpidem plus fluconazole. RESULTS: Mean apparent oral clearance of zolpidem when given with placebo was 422 mL/min, and elimination half-life was 1.9 hours. Clearance was significantly reduced to 250 mL/min when zolpidem was given with ketoconazole, and half-life was prolonged to 2.4 hours. Coadministration of zolpidem with itraconazole or fluconazole also reduced clearance (320 and 338 mL/min), but differences compared to the zolpidem plus placebo treatment did not reach significance. Zolpidem-induced benzodiazepine agonist effects (increased electrocardiographic beta activity, digit-symbol substitution test impairment, and delayed recall) during the first 4 hours after dosage were enhanced by ketoconazole but not by itraconazole or fluconazole. CONCLUSION: Coadministration of zolpidem with ketoconazole impairs zolpidem clearance and enhances its benzodiazepine-like agonist pharmacodynamic effects. Itraconazole and fluconazole had a small influence on zolpidem kinetics and dynamics. The findings are consistent with in vitro studies of differentially impaired zolpidem metabolism by azole derivatives.


Subject(s)
Antifungal Agents/pharmacology , Hypnotics and Sedatives/pharmacology , Pyridines/pharmacology , Administration, Oral , Adult , Antifungal Agents/administration & dosage , Antifungal Agents/blood , Antifungal Agents/pharmacokinetics , Cross-Over Studies , Double-Blind Method , Female , Fluconazole/pharmacology , Half-Life , Humans , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/blood , Hypnotics and Sedatives/pharmacokinetics , Itraconazole/pharmacology , Ketoconazole/pharmacology , Male , Pyridines/administration & dosage , Pyridines/blood , Pyridines/pharmacokinetics , Reference Values , Zolpidem
8.
J Anal Toxicol ; 21(5): 388-92, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9288593

ABSTRACT

Zolpidem, an imidazopyradine hypnotic agent, can be quantitated by high-performance liquid chromatography (HPLC) with fluorescence detection. After the addition of a structurally related internal standard (propyl-zolpidem), plasma samples were double-extracted at neutral pH with toluene-isoamyl alcohol or benzene-isoamyl alcohol. The organic extracts were evaporated to dryness, reconstituted with mobile phase, and analyzed by HPLC using a C-18 reversed-phase column, a mobile phase of acetonitrile-50mM potassium dihydrogen phosphate (50:50), and fluorescence detection with excitation and emission wavelengths of 254 and 390 nm, respectively. The lower limit of reliable quantitation was in the range of 1-2.5 ng/mL. The method is applicable to single-dose pharmacokinetic studies of zolpidem in humans.


Subject(s)
Hypnotics and Sedatives/blood , Hypnotics and Sedatives/pharmacokinetics , Pyridines/blood , Pyridines/pharmacokinetics , Adult , Chromatography, High Pressure Liquid/methods , Drug Administration Schedule , Evaluation Studies as Topic , Female , Humans , Male , Sensitivity and Specificity , Spectrometry, Fluorescence/methods , Zolpidem
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