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ABSTRACT: Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. Efavirenz stereoselectively decreased methadone plasma concentrations 50-70%. Methadone systemic and oral clearances, hepatic clearance and extraction ratio, N-demethylation, and metabolite formation clearance were stereoselectively increased two- to threefold. Bioavailability decreased. Efavirenz shifted methadone concentration-miosis curves leftward and upward. Efavirenz induced hepatocyte CYP2B6 and CYP3A4 expression, activity, and methadone N-demethylation. Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.
Clinical Pharmacology & Therapeutics 03/2012; 91(4):673-84. · 6.04 Impact Factor
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ABSTRACT: Systemic and oral clearances of alfentanil (ALF) are in vivo probes for hepatic and first-pass cytochrome P450 (CYP) 3A. Both ALF single-point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC) and clearance and are minimal and noninvasive CYP3A probes. This investigation determined ALF sensitivity for detecting graded CYP3A induction and compared it with that of midazolam (MDZ). Twelve volunteers (sequential crossover) received 0, 5, 10, 25, or 75 mg oral rifampin for 5 days. MDZ and ALF were given intravenously and orally on sequential days. Dark-adapted pupil diameter was measured with blood sampling. Graded rifampin decreased plasma MDZ AUCs to 83, 76, 62, and 59% (intravenous (i.v.)) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma MDZ and ALF AUCs. Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A.
Clinical Pharmacology & Therapeutics 07/2011; 90(1):100-8. · 6.04 Impact Factor
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ABSTRACT: Alfentanil (ALF) is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations, and noninvasive pupil diameter change (miosis). Assessing intravenous (i.v.) and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and i.v. unlabeled ALF to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. ALF disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma ALF concentrations and area under the curve (AUC), clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs. simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.
Clinical Pharmacology & Therapeutics 02/2011; 89(4):562-70. · 6.04 Impact Factor
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ABSTRACT: Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.
Clinical Pharmacology & Therapeutics 11/2008; 84(4):497-505. · 6.04 Impact Factor
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ABSTRACT: Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.
Clinical Pharmacology & Therapeutics 11/2008; 84(4):506-12. · 6.04 Impact Factor
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E D Kharasch
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ABSTRACT: Problems with organ toxicity from the halogenated volatile anesthetics have influenced clinical practice, anesthetic selection, and drug development for half a century.(1,2) In turn, investigations that elucidated the mechanisms of volatile anesthetics adverse effects identified new mechanisms, provided remarkable insights into human toxicology, and represented seminal contributions to clinical pharmacology. This review focuses on adverse organ effects (hepatic, renal, and others) that are attributable to anesthetic metabolism and/or degradation. Routine reversible effects on pulmonary, cardiac, and other organ functions are not addressed.
Clinical Pharmacology & Therapeutics 08/2008; 84(1):158-62. · 6.04 Impact Factor
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ABSTRACT: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
Clinical Pharmacology & Therapeutics 02/2008; 83(1):77-85. · 6.04 Impact Factor
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ABSTRACT: The hepatic and first-pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark-adapted pupil diameters were determined coincident with blood sampling. In CYP3A5(*)3/(*)3 (n=62), (*)1/(*)3 (n=28), and (*)1/(*)1 (n=8) genotypes, systemic clearances of ALF were 4.6+/-1.8, 4.8+/-1.7, and 3.9+/-1.7 ml/kg/min and those of MDZ were 7.8+/-2.3, 7.7+/-2.3, and 6.0+/-1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8+/-7.2, 13.3+/-6.1, and 12.6+/-8.2 ml/kg/min for ALF and 35.2+/-19.0, 36.4+/-15.7, and 29.4+/-9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.
Clinical Pharmacology & Therapeutics 11/2007; 82(4):410-26. · 6.04 Impact Factor
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ABSTRACT: Purpose: Ritonavir (RIT) decreases methadone (M) conc. & causes withdrawal. M metabolism is attributed mainly to CYP3A. Acute & chronic RIT are said to cause CYP3A inhibition & induction, respectively. We tested whether acute & chronic RIT would inhibit & induce M elimination, due to commensurate changes in CYP3A. Alfentanil (ALF) was the CYP3A probe.Methods: Volunteers (12) were studied in a nonrandomized crossover. On 3 consecutive days they received ALF 15 |[iacute]|g/kg IV, ALF 43 |[mu]|g/kg PO, & M-HCl (11 mg PO + 6 mg IV). They then took RIT, 200 mg po TID |[times]| 1d, 300 mg BID x 6d, then 400 mg BID x 13d. Subjects received ALF 4.3 |[mu]|g/kg PO on RIT day 2, M (11 mg PO + 6 mg IV) on RIT day 3, & ALF 4.3 |[mu]|g/kg PO, ALF 5 |[mu]|g/kg IV, & M on RIT days 15,16, 17. Dark-adapted pupil diameters were measured after opioid dosing.Results: Average dose-normalized AUC for IV ALF miosis was increased from 6 to 24 mm-hr/mg by acute RIT. Average dose-normalized AUC for PO ALF miosis was increased from 2.1 to 37 and 19 mm-hr/mg by acute and chronic RIT, respectively. Average AUC for M miosis was increased from 89 to 115 mm-hr by acute RIT, but returned to 78 after chronic RIT.Conclusions: Miosis was a utilitarian method to measure M & ALF disposition. RIT was a profound (first-pass|[Gt]| hepatic) CYP3A inhibitor. Acute & chronic RIT inhibited & mildly increased M elimination, but the latter was not due to CYP3A induction. M may be metabolized by P450s in addition to CYP3A, which are induced by RIT.
Clinical Pharmacology & Therapeutics 01/2004; 75(2):P96-P96. · 6.04 Impact Factor
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ABSTRACT: Purpose: Systemic clearance of IV alfentanil (ALF) is an in vivo probe for hepatic CYP3A, miosis is a surrogate for plasma ALF, & IV ALF miosis is a suitable noninvasive probe for hepatic CYP3A. This study determined whether oral ALF & miosis could probe first-pass CYP3A activity. Midazolam (MDZ) was also used to measure CYP3A.Methods: Volunteers (10) were studied in a randomized 9-way crossover, after 5d rifampin (liver & gut CYP3A induction), troleandomycin (TAO, liver & gut CYP3A inhibition), grapefruit juice (GFJ, selective gut CYP3A inhibition), or nothing (control). They received MDZ 1mg IV then (1 hr later) ALF 15 íg/kg IV; at another visit 3 mg oral MDZ then (1 hr) oral ALF (23 or 60 íg/kg). Blood (MDZ & ALF by LCMS) & dark-adapted pupil diameters were measured & analyzed (noncompartmental).Results: Bioavailability (F), hepatic extraction (EH) & GI availability (FGI) were 0.26, 0.55 & 0.60 for MDZ and 0.42, 0.29 & 0.62 for ALF. After rifampin, TAO & GFJ, ALF F was 0.02, 1 & 0.67; EH was 0.71, 0.04 & 0.26. FGI was 0.07, 1 & 0.92. There were excellent correlations between IV ALF & MDZ systemic clearance (r2=0.92), oral ALF & MDZ CL/F (r2=0.97), and dose-adjusted AUCs for miosis & plasma ALF.Conclusions: Systemic & oral CL of IV & oral ALF are excellent in vivo probes for hepatic & first-pass CYP3A activity & interactions. Miosis was an acceptable surrogate for plasma ALF. ALF miosis may be a suitable noninvasive in vivo probe for hepatic & first-pass CYP3A.
Clinical Pharmacology & Therapeutics - CLIN PHARMACOL THER. 01/2004; 75(2).
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ABSTRACT: Purpose: Systemic & oral clearances of IV & oral alfentanil (ALF) are in vivo probes for hepatic & first-pass CYP3A. ALF effect (miosis) is a surrogate for plasma ALF. ALF miosis can detect profound (>70%) hepatic CYP3A inhibition by TAO. This study determined the sensitivity of ALF miosis for detecting hepatic & intestinal CYP3A inhibition (targeted 12, 25 & 50% inhibition). Midazolam (MDZ) measured CYP3A activity.Methods: Volunteers (12) in a randomized 4-way crossover received 0, 100, 200, or 400 mg oral fluconazole (FCZ), then (2 hr later) MDZ 1 mg IV then (1 hr) ALF 15 íg/kg IV. Next day, they received FCZ, then (2 hr) 3 mg oral MDZ then (1 hr) oral ALF (40 íg/kg). Venous plasma (MDZ & ALF by LCMS) and dark-adapted pupil diameters were obtained & analyzed noncompartmentally.Results: Plasma AUC ratios (FCZ/control) after 100, 200 & 400 mg FCZ were 1.2, 1.3* & 1.7* for IV MDZ, and 1.2, 1.5* & 2.0* for IV ALF (*p
Clinical Pharmacology & Therapeutics - CLIN PHARMACOL THER. 01/2004; 75(2).
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ABSTRACT: Cytochrome P4502E1(CYP2E1)-mediated oxidation of halothane to a reactive intermediate (trifluoroacyl chloride) that covalently binds to hepatic proteins forming trifluoroacetylated neoantigens is believed to be the initiating event in a complex immunologic cascade culminating in antibody formation and severe hepatic necrosis ('halothane hepatitis') in susceptible patients. Trifluoroacyl chloride may also hydrolyze to the stable metabolite trifluoroacetic acid (TFA). CYP2E1 inactivation by disulfiram or its primary metabolite, diethyldithiocarbamate, inhibits human halothane oxidation to TFA in vitro and in vivo. Nevertheless, disulfiram effects on hepatic protein trifluoroacetylation by halothane in vivo are unknown. This investigation tested the hypotheses that disulfiram prevents halothane-dependent protein trifluoroacetylation in vivo, and that TFA represents a biomarker for hepatic protein trifluoroacetylation.
Rats were pretreated with isoniazid (CYP2E1 induction), isoniazid followed by disulfiram (CYP2E1 inhibition), or nothing (controls), then anesthetized with halothane or nothing (controls). Plasma and urine TFA were quantified by ion HPLC; hepatic microsomal TFA-proteins were analyzed by Western blot.
CYP2E1 induction increased both TFA and TFA-protein formation compared with uninduced halothane-treated rats. Disulfiram, even after CYP2E1 induction, nearly abolished both TFA and TFA-protein formation. Pretreatments similarly affected both TFA and TFA-protein formation across all groups.
Disulfiram inhibition of CYP2E1-mediated halothane oxidation prevents hepatic protein trifluoroacetylation. Based on the concordance between TFA and TFA-protein formation, TFA appears to be a valid biomarker for TFA-protein formation. Disulfiram inhibition of human halothane oxidation in vivo, previously assessed by diminished TFA formation, probably also confers inhibition of hepatic TFA-protein formation.
Acta Anaesthesiologica Scandinavica 08/2003; 47(6):765-70. · 2.19 Impact Factor
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Y S Lin,
G F Lockwood,
M A Graham,
W R Brian,
C M Loi,
M R Dobrinska,
D D Shen,
P B Watkins,
G R Wilkinson, E D Kharasch,
K E Thummel
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ABSTRACT: We investigated whether a single plasma midazolam concentration could serve as an accurate predictor of total midazolam clearance, an established in-vivo probe measure of cytochrome P450 3A (CYP3A) activity. In a retrospective analysis of data from 224 healthy volunteers, non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time curves following intravenous (IV) and/or oral administration. Based on statistical moment theory, the concentration at the mean residence time (MRT) should be the best predictor of the total area under the curve (AUC). Following IV or oral midazolam administration, the average MRT was found to be approximately 3.5 h, suggesting that the optimal single sampling time to predict AUC was between 3 and 4 h. Since a 4-h data point was common to all studies incorporated into this analysis, we selected this time point for further investigation. The concentrations of midazolam measured 4 h after an IV or oral dose explained 80 and 91% of the constitutive interindividual variability in midazolam AUC, respectively. The 4-h midazolam measurement was also an excellent predictor of drug-drug interactions involving CYP3A induction and inhibition. Compared with baseline values, the direction and magnitude of change in midazolam AUC and the 4-h concentration were completely concordant for all study subjects. We conclude that a single 4-h midazolam concentration following IV or oral administration represents an accurate marker of CYP3A phenotype under constitutive and modified states. Moreover, the single-point approach offers an efficient means to phenotype and identify individuals with important genetic polymorphisms that affect CYP3A activity.
Pharmacogenetics 01/2002; 11(9):781-91.
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ABSTRACT: Sevoflurane degradation by carbon dioxide absorbents during low-flow anesthesia forms the haloalkene Compound A, which causes nephrotoxicity in rats. Numerous studies have shown no effects of Compound A formation on postoperative renal function after moderate-duration (3-4 h) low-flow sevoflurane; however, effects of longer exposures remain unresolved. We compared renal function after long-duration low-flow (<1 L/min) sevoflurane and isoflurane anesthesia in consenting surgical patients with normal renal function. To maximize degradant exposure, Baralyme was used, and anesthetic concentrations were maximized (no nitrous oxide and minimal opioids). Inspired and expired Compound A concentrations were quantified. Blood and urine were obtained for laboratory evaluation. Sevoflurane (n = 28) and isoflurane (n = 27) groups were similar with respect to age, sex, weight, ASA status, and anesthetic duration (9.1 +/- 3.0 and 8.2 +/- 3.0 h, mean +/- SD) and exposure (9.2 +/- 3.6 and 9.1 +/- 3.7 minimum alveolar anesthetic concentration hours). Maximum inspired Compound A was 25 +/- 9 ppm (range, 6-49 ppm), and exposure (area under the concentration-time curve) was 165 +/- 95 (35-428) ppm. h. There was no significant difference between anesthetic groups in 24- or 72-h serum creatinine, blood urea nitrogen, creatinine clearance, or 0- to 24-h or 48- to 72-h urinary protein or glucose excretion. Proteinuria and glucosuria were common in both groups. There was no correlation between Compound A exposure and any renal function measure. There was no difference between anesthetic groups in 24- or 72-h aspartate aminotransferase or alanine aminotransferase. These results show that the renal and hepatic effects of long-duration low-flow sevoflurane and isoflurane were similar. No evidence for low-flow sevoflurane nephrotoxicity was observed, even at high Compound A exposures as long as 17 h. Proteinuria and glucosuria were common and nonspecific postoperative findings. Long-duration low-flow sevoflurane seems as safe as long-duration low-flow isoflurane anesthesia. IMPLICATIONS: Postoperative renal function after long-duration low-flow sevoflurane (with Compound A exposures greater than those typically reported) and isoflurane anesthesia were not different, as assessed by serum creatinine, blood urea nitrogen, and urinary excretion of protein and glucose. This suggests that low-flow sevoflurane is as safe as low-flow isoflurane, even at long exposures.
Anesthesia & Analgesia 01/2002; 93(6):1511-20, table of contents. · 3.29 Impact Factor
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ABSTRACT: Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) is a fluorinated alkene formed by degradation of the volatile anesthetic sevoflurane in anesthesia machines. FDVE is nephrotoxic in rats and undergoes glutathione-dependent conjugation to form two alkane (G1, G2) and two alkene glutathione S-conjugates (G3, G4), cleavage to cysteine S-conjugates, and beta-lyase-catalyzed metabolism to reactive thionoacyl fluorides, which may react with cellular macromolecules to cause nephrotoxicity. Although similar metabolites have been identified in human urine in vivo, little is known about sites and mechanisms of GSH conjugation in humans. This investigation quantified FDVE-GSH conjugates formed by human hepatic and renal microsomal and cytosolic fractions and blood in vitro. LC-MS/MS analysis identified all four GSH conjugates (G1-G4) formed in all human subcellular fractions. Quantitative analysis indicated that the relative order of formation was G2 > G1 > G4 > G3 with human liver and kidney subfractions. In blood, the order was G1 > G4 > G2 > G3. These results demostrate that FDVE undergoes GSH-dependent conjugation in human liver and kidney microsomes and cytosol as well as blood, which may account for the detection of corresponding mercapturic acids in the urine of patients exposed to FDVE.
Toxicology and Applied Pharmacology 12/2001; 177(2):85-93. · 4.45 Impact Factor
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ABSTRACT: Bispectral Index (BIS) has been used to measure sedation depth. Ideally, to guide anesthetic management, range of BIS scores at different sedation levels should not overlap, and BIS should be independent of drug used. This study assessed ability of BIS to predict sedation depth between sevoflurane, propofol, and midazolam. Quality of recovery was also compared.
Patients undergoing surgery with local or regional anesthesia and sedation were randomized to sevoflurane (n = 23), midazolam (n = 21), or propofol (n = 22). Sedation was titrated to Observers's Assessment of Alertness-Sedation score of 3 (responds slowly to voice). BIS and Observers's Assessment of Alertness-Sedation were measured every 5 min. BIS prediction probability (PK) was compared between drugs. Recovery was assessed by BIS and Digit Symbol Substitution and memory tests.
Bispectral Index of responders to voice was significantly different from nonresponders (86 +/- 10 vs. 74 +/- 14, mean +/- SD; P < 0.001) However, wide variability and overlap in BIS were observed (25th-75th percentile, responders vs. non-responders: 79-96 vs. 65-83). BIS of responders was different for sevoflurane versus propofol and midazolam. BIS was a better predictor of propofol sedation than sevoflurane or midazolam (PK = 0.87 +/- 0.11, 0.76 +/- 0.01, and 0.69 +/- 0.02, respectively; P < 0.05). At 10 min after the procedure, 76, 48, and 24% of sevoflurane, propofol, midazolam patients, respectively, returned to baseline Digit Symbol Substitution scores (P < 0.05). Excitement-disinhibition occurred in 70, 36, and 5% of sevoflurane, propofol, and midazolam patients, respectively (P < 0.05).
Individual BIS scores demonstrate significant variability, making it difficult to predict sedation depth. The relation between BIS and sedation depth may not be independent of anesthetic agent. Quality of recovery was similar between drugs, but excitement occurred frequently with sevoflurane.
Anesthesiology 12/2001; 95(5):1151-9. · 5.36 Impact Factor
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ABSTRACT: The opioid alfentanil is a CYP3A4 substrate whose plasma clearance depends exclusively on hepatic CYP3A4 activity. Alfentanil clearance is an excellent in vivo probe for hepatic CYP3A4 activity and drug interactions in humans. However, such pharmacokinetic studies are invasive and time-consuming, and they require extensive analytical effort. This investigation tested the hypothesis that alfentanil-induced miosis (drug effect) can be used as a surrogate measure for alfentanil plasma concentrations and that alfentanil effect clearance will reflect plasma clearance; thus alfentanil can serve as a noninvasive probe for hepatic CYP3A4.
Six healthy volunteers were studied in a 3-way randomized crossover design. Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 microg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control. Dark-adapted pupil diameter and dynamic light response were measured coincident with venous blood sampling for up to 8 hours. Midazolam and alfentanil were quantified by gas chromatography-mass spectrometry. Plasma concentrations of alfentanil and midazolam (an additional CYP3A4 probe) and pupil diameter versus time data were analyzed by use of noncompartmental modeling. Pupil diameter change was analyzed analogously to determine the area under the alfentanil effect (miosis)-time curve (AUEC), effect clearance (CL(miosis)), and effect half-time.
Compared with control, CYP3A4 induction and inhibition significantly altered the clearances of alfentanil (2.8 +/- 1.4, 5.3 +/- 1.0, and 0.42 +/- 0.1 ml/kg/min, respectively; P <.05 versus control) and midazolam. Dark-adapted resting diameter (in millimeters) was the best measure of alfentanil pupil effects. Alfentanil-dependent miosis was significantly altered by CYP3A4 modulation, and log(diameter(0) - diameter(t)) versus time curves resembled alfentanil plasma disposition. AUEC(infinity) values after control, CYP3A4 induction, and inhibition were 280 +/- 150, 120 +/- 22, and 1030 +/- 240 mm x min, respectively (P <.05 versus control). Effect clearances (CL(miosis)) were 4.2 +/- 1.3, 8.8 +/- 2.4, and 1.2 +/- 0.8 microg/mm x min, respectively, and effect half-times were 62 +/- 23, 34 +/- 27, and 211 +/- 35 minutes, respectively (P <.05 versus control). CL(miosis) was significantly correlated with plasma clearances of alfentanil (r = 0.77, P <.001) and midazolam (r = 0.80; P <.001).
Alfentanil effect (miosis) may be a sensitive and reliable surrogate for plasma alfentanil concentrations. Alfentanil effect kinetics may be used as a noninvasive surrogate for conventional pharmacokinetics. CL(miosis) appears to be a suitable noninvasive in vivo probe for hepatic CYP3A4 activity, and it merits further investigation.
Clinical Pharmacology & Therapeutics 12/2001; 70(6):505-17. · 6.04 Impact Factor
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ABSTRACT: Several reports indicate that fluvoxamine decreases the clearance of cytochrome P4501A2 (CYP1A2) substrates. This study compared in vitro and in vivo inhibition potencies of fluvoxamine toward CYP1A2 with an approach based on inhibition constants (K(i)) determined in vitro and in vivo.
In vitro inhibition constant values were determined with human liver microsomes and complementary deoxyribonucleic acid-expressed CYP1A2 (supersomes). Fluvoxamine in vivo inhibition constants (K(i)iv) for CYP1A2 were obtained from an investigation of single-dose theophylline (250 mg) disposition in 9 healthy volunteers receiving steady-state (9 days) fluvoxamine at 3 doses (0, 25, or 75 mg/d) in a randomized crossover design.
In vitro K(i) values based on total inhibitor concentrations were 177 +/- 56 nmol/L, 121 +/- 21 nmol/L, and 52 +/- 13 nmol/L in human liver microsomes with 1 mg/ml protein and 0.5 mg/ml protein and in supersomes with 0.3 mg/ml protein, respectively. The corresponding in vitro K(i) values based on unbound fluvoxamine concentrations were 35 nmol/L, 36 nmol/L, and 36 nmol/L. The ratio of 1-methyluric acid formation clearances (control/inhibited) in 8 subjects was positively correlated with fluvoxamine concentration (r (2) = 0.87; P <.001) with an intercept near 1. Mean values for K(i)iv based on total and unbound plasma concentrations at steady state were 25.3 nmol/L (range, 14-39 nmol/L) and 3.6 nmol/L (range, 2.4-5.9 nmol/L), respectively.
Comparison of in vitro and in vivo K(i) values based on unbound fluvoxamine concentrations suggests that fluvoxamine inhibition potency is approximately 10 times greater in vivo than in vitro.
Clinical Pharmacology & Therapeutics 11/2001; 70(5):415-24. · 6.04 Impact Factor
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ABSTRACT: Methadone and levo-alpha-acetylmethadol (LAAM) are opioid agonists used for analgesia and preventing opiate withdrawal. Methadone is sequentially N-demethylated to the inactive metabolites 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP). LAAM is essentially a prodrug that undergoes bioactivation via sequential N-demethylation to levo-alpha-acetyl-N-normethadol (nor-LAAM) and levo-alpha-acetyl-N,N-dinormethadol (dinor-LAAM). Methadone and LAAM are metabolized by CYP3A4 in human liver. Since they are administered orally, and CYP3A4 is expressed in human intestine, we tested the hypotheses that human intestine can metabolize methadone and LAAM, and evaluated the participation of CYP3A4. Intestinal microsomal methadone N-demethylation exhibited hyperbolic noncooperative kinetics and biphasic Eadie-Hofstee plots. Using a dual-enzyme Michaelis-Menten model, K(m) values were 11 and 1200 microM for EDDP and 23 and 930 microM for EMDP formation, respectively. CYP3A4 inhibitors (troleandomycin and ketoconazole) inhibited EDDP and EMDP formation by >70%. Methadone N-demethylation by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; K(m) values were 10 and 1100 microM for EDDP and 20 and 1000 microM for EMDP formation. Intestinal microsomal LAAM and nor-LAAM N-demethylation also exhibited hyperbolic kinetics and biphasic Eadie-Hofstee plots. K(m) values were 21 and 980 microM for nor-LAAM from LAAM and 18 and 1200 microM for dinor-LAAM from nor-LAAM. Troleandomycin and ketoconazole inhibited N-demethylation by >70%. LAAM and nor-LAAM metabolism by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; K(m) values were 8 and 1300 microM, 6 and 950 microM, respectively. Predicted in vivo intestinal extraction of methadone and LAAM is 21 and 33%, respectively. We conclude that methadone, LAAM, and nor-LAAM are metabolized by human intestinal microsomes; CYP3A4 is the predominant cytochrome P450 isoform; CYP3A4-catalyzed methadone, LAAM, and nor-LAAM metabolism is characterized by noncooperative, multisite kinetics; and intestinal metabolism may contribute to presystemic methadone inactivation and LAAM bioactivation.
Journal of Pharmacology and Experimental Therapeutics 09/2001; 298(3):1021-32. · 3.83 Impact Factor
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ABSTRACT: Halothane is extensively (approximately 50%) metabolized in humans and undergoes both oxidative and reductive cytochrome P450-catalyzed hepatic biotransformation. Halothane is reduced under low oxygen tensions by CYP2A6 and CYP3A4 in human liver microsome to an unstable free radical, and then to the volatile metabolites chlorodifluoroethene (CDE) and chlorotrifluoroethane (CTE). The free radical is also thought to initiate lipid peroxidation. Halothane-dependent lipid peroxidation has been shown in animals in vitro and in vivo but has not been evaluated in humans. This investigation tested the hypothesis that halothane causes lipid peroxidation in human liver microsomes, identified P450 isoforms responsible for halothane-dependent lipid peroxidation, and tested the hypothesis that lipid peroxidation is prevented by inhibiting halothane reduction.
Halothane metabolism was determined using human liver microsomes or cDNA-expressed P450. Lipid peroxidation was quantified by malondialdehyde (MDA) formation using high-pressure liquid chromatography-ultraviolet analysis of the thiobarbituric acid-MDA adduct. CTE and CDE were determined by gas chromatography-mass spectrometry.
Halothane caused MDA formation in human liver microsomes at rates much lower than in rat liver microsomes. Human liver microsomal MDA production exhibited biphasic enzyme kinetics, similar to CDE and CTE production. MDA production was inhibited by the CYP2A6 inhibitor methoxsalen but not by the CYP3A4 inhibitor troleandomycin. Halothane-dependent MDA production was catalyzed by cDNA-expressed CYP2A6 but not CYP3A4 or P450 reductase alone. CYP2A6-catalyzed MDA production was inhibited by methoxsalen or anti-CYP2A6 antibody.
Halothane causes lipid peroxidation in human liver microsomes, which is catalyzed by CYP2A6, and inhibition of halothane reduction prevents halothane-dependent lipid peroxidation in vitro.
Anesthesiology 09/2001; 95(2):509-14. · 5.36 Impact Factor
