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patient disposition
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Articles
Tae Kyun Kim, M.D., Shinju Obara, M.D., Talmage D. Egan, M.D., The Remifentanil Pharmacokinetics in Obesity Investigators
Journal:
Anesthesiology
Anesthesiology. June 2017; 126(6):1019–1032
Published: June 2017
Abstract
Background The influence of obesity on the pharmacokinetic (PK) behavior of remifentanil is incompletely understood. The aim of the current investigation was to develop a new population PK model for remifentanil that would adequately characterize the influence of body weight (among other covariates, e.g. , age) on the disposition of remifentanil in the general adult population. We hypothesized that age and various indices of body mass would be important covariates in the new model. Methods Nine previously published data sets containing 4,455 blood concentration measurements from 229 subjects were merged. A new PK model was built using nonlinear mixed-effects modeling. Satisfactory model performance was assessed graphically and numerically; an internal, boot-strapping validation procedure was performed to determine the CIs of the model. Results Body weight, fat-free body mass, and age (but not body mass index) exhibited significant covariate effects on certain three-compartment model parameters. Visual and numerical assessments of model performance were satisfactory. The bootstrap procedure showed satisfactory CIs on all of the model parameters. Conclusions A new model estimated from a large, diverse data set provides the PK foundation for remifentanil dosing calculations in adult obese and elderly patients. It is suitable for use in target-controlled infusion systems and pharmacologic simulation.
Articles
Articles
Evan D. Kharasch, M.D., Ph.D., Pamela Sheffels Bedynek, B.S., Christine Hoffer, B.A., Alysa Walker, B.S., Dale Whittington, B.S.
Journal:
Anesthesiology
Anesthesiology. February 2012; 116(2):432–447
Published: February 2012
Abstract
Background Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine). Methods Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis. Results Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir. Conclusions Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.
Articles
Hisayo O. Morishima, M.D., Ph.D., Atsuro Ishizaki, M.D., Ph.D., Yi Zhang, M.D., Robert A. Whittington, M.D., Raymond F. Suckow, Ph.D., Thomas B. Cooper, M.A.
Journal:
Anesthesiology
Anesthesiology. October 2000; 93(4):1069–1074
Published: October 2000
Abstract
Background This study was designed to determine the disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments, using multiple sampling time points in chronically prepared awake pregnant rats. Methods All animals received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 h after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. Results The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefold higher in the maternal and 11-fold higher than in the fetal plasma. At 4 h after dosing, bupivacaine was no longer detectable in any maternal and fetal samples, whereas 3'-hydroxybupivacaine was still present in all tissues except the fetal plasma and heart. Conclusions These data indicate that a considerable amount of bupivacaine is taken up by both sides of the placenta, as well as the amnion and myometrium. 3'-Hydroxybupivacaine was present in all tissues except the fetal plasma and heart samples, even after the parent compound became no longer detectable. Whether this slow elimination of 3'-hydroxybupivacaine causes any adverse effects on the fetus-newborn needs to be explored.
Articles
Yan-Ling He, Ph.D., Hiroshi Ueyama, M.D., Chikara Tashiro, M.D., Takashi Mashimo, M.D., Ikuto Yoshiya, M.D.
Journal:
Anesthesiology
Anesthesiology. October 2000; 93(4):986–991
Published: October 2000
Abstract
Background The lungs have been mentioned as a possible site contributing to the extrahepatic clearance of propofol. The objective of the present study was to clarify the pulmonary disposition of propofol directly in human lungs by investigating both the first-pass uptake and pulmonary extraction at pseudo-steady state. Methods Nine patients were enrolled in the first-pass uptake study. Propofol (5 mg) and indocyanine green (ICG; 15 mg) were simultaneously administered via a central venous catheter within 1 s, and sequential arterial blood samples were obtained from the radial artery at 1-s intervals up to 45 s. Eleven patients were included in the infusion study, and propofol was infused via the jugular vein at a rate of 50 microgram. kg-1. min-1. Blood samples were simultaneously collected from pulmonary and radial arteries up to 60 min. Results A pronounced difference in the dilution curves between propofol and ICG was observed, and 28.4 +/- 11.6% (mean +/- SD) of propofol was taken up during the single passage through the human lung. The mean pulmonary transit time of propofol (31.3 +/- 6.0 s) was significantly longer than that of ICG (22.4 +/- 2.7 s; P < 0.01), indicating that some of the propofol trapped by lungs returned to the circulation by back diffusion. In the constant infusion study, no significant differences were observed with the plasma concentrations of propofol between pulmonary and radial arteries except for that at 2 min. The area under the curve of pulmonary and radial arterial concentration curves to 60 min were 59.1 +/- 14.8 and 56.8 +/- 12.5 microg. ml-1. min-1, respectively. No significant difference was observed with the area under the curve, suggesting that metabolism was not involved in the pulmonary uptake in human lungs. Conclusions Most of the propofol that undergoes pulmonary uptake during the first pass was released back to the circulation by back diffusion. Metabolism was not involved in the pulmonary uptake in human lungs.
Articles
Evan D. Kharasch, MD, PhD, Michael Russell, MD, PhD, Douglas Mautz, PhD, Kenneth E. Thummel, PhD, Kent L. Kunze, PhD, T. Andrew Bowdle, MD, PhD, Kathy Cox, BS
Journal:
Anesthesiology
Anesthesiology. July 1997; 87(1):36–50
Published: July 1997
Abstract
Background There is considerable unexplained variability in alfentanil pharmacokinetics, particularly systemic clearance. Alfentanil is extensively metabolized in vivo, and thus systemic clearance depends on hepatic biotransformation. Cytochrome P450 3A4 was previously shown to be the predominant P450 isoform responsible for human liver microsomal alfentanil metabolism in vitro. This investigation tested the hypothesis that P450 3A4 is responsible for human alfentanil metabolism and clearance in vivo. Methods Nine healthy male volunteers who provided institutionally approved written informed consent were studied in a three-way randomized crossover design. Each subject received alfentanil (20 micrograms/kg given intravenously) 30 min after midazolam (1 mg injected intravenously) on three occasions: control; high P450 3A4 activity (rifampin induction); and low P450 3A4 activity (selective inhibition by troleandomycin). Midazolam is a validated selective in vivo probe for P450 3A4 activity. Venous blood was sampled for 24 h and plasma concentrations of midazolam and alfentanil and their primary metabolites 1'-hydroxymidazolam and noralfentanil were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were determined by two-stage analysis using both noncompartmental and three-compartment models. Results Plasma alfentanil concentration-time profiles depended significantly on P450 3A4 activity. Alfentanil noncompartmental clearance was 5.3 +/- 2.3, 14.6 +/- 3.8, and 1.1 +/- 0.5 ml.kg-1.min-1, and elimination half-life was 58 +/- 13, 35 +/- 7, and 630 +/- 374 min, respectively, in participants with normal (controls), high (rifampin), and low (troleandomycin) P450 3A4 activity (means +/- SD; P < 0.05 compared with controls). Multicompartmental modeling suggested a time-dependent inhibition-resynthesis model for troleandomycin effects on P450 3A4 activity, characterized as k10(t) = k10[1-phi e-alpha(t-tzero)], where k10(t) is the apparent time-dependent rate constant, k10 is the uninhibited rate constant, phi is the fraction of P450 3A4 inhibited, and alpha is the apparent P450 3A4 reactivation rate. Alfentanil clearance was calculated as V1 k10 for controls and men receiving rifampin, and as V1.average k10(t) for men receiving troleandomycin. This clearance was 4.9 +/- 2.1, 13.2 +/- 3.6, and 1.5 +/- 0.8 ml.kg-1.min-1, respectively, in controls and in men receiving rifampin or troleandomycin. There was a significant correlation (r = 0.97, P < 0.001) between alfentanil systemic clearance and P450 3A4 activity. Conclusions Modulation of P450 3A4 activity by rifampin and troleandomycin significantly altered alfentanil clearance and disposition. These results strongly suggest that P450 3A4 is the major isoform of P450 responsible for clinical alfentanil metabolism and clearance. This observation, combined with the known population variability in P450 3A4 activity, provides a mechanistic explanation for the interindividual variability in alfentanil disposition. Furthermore, known susceptibility of human P450 3A4 activity to induction and inhibition provides a conceptual framework for understanding and predicting clinical alfentanil drug interactions. Finally, human liver microsomal alfentanil metabolism in vitro is confirmed as an excellent model for human alfentanil metabolism in vivo.
Articles
Journal:
Anesthesiology
Anesthesiology. June 1995; 82(6):1369–1378.
Published: June 1995
Abstract
Background Sevoflurane has low blood and tissue solubility and is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Although sevoflurane uptake and distribution and fluoride formation have been described, the pharmacokinetics of HFIP formation and elimination are incompletely understood. This investigation comprehensively characterized the simultaneous disposition of sevoflurane, fluoride, and HFIP. Methods Ten patients within 30% of ideal body weight who provided institutional review board-approved informed consent received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction, after which anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Sevoflurane and unconjugated and total HFIP concentrations in blood were determined during anesthesia and for 8 h thereafter. Plasma and urine fluoride and total HFIP concentrations were measured during and through 96 h after anesthetic administration. Fluoride and HFIP were quantitated using an ion-selective electrode and by gas chromatography, respectively. Results The total sevoflurane dose, calculated from the pulmonary uptake rate, was 88.8 +/- 9.1 mmol. Sevoflurane was rapidly metabolized to the primary metabolites fluoride and HFIP, which were eliminated in urine. HFIP circulated in blood primarily as a glucuronide conjugate, with unconjugated HFIP < or = 15% of total HFIP concentrations. In blood, peak unconjugated HFIP concentrations were less than 1% of peak sevoflurane concentrations. Apparent renal fluoride and HFIP clearances (mean +/- SE) were 51.8 +/- 4.5 and 52.6 +/- 6.1 ml/min, and apparent elimination half-lives were 21.4 +/- 2.8 and 20.1 +/- 2.6 h, respectively. Renal HFIP and net fluoride excretion were 4,300 +/- 540 and 3,300 +/- 540 mumol. Compared with the estimated sevoflurane uptake, 4.9 +/- 0.5% of the dose taken up was eliminated in the urine as HFIP. For fluoride, 3.7 +/- 0.4% of the sevoflurane dose taken up was eliminated in the urine, which, because a portion of fluoride is sequestered in bone, corresponded to approximately 5.6% of the sevoflurane dose metabolized to fluoride. Conclusions Sevoflurane was rapidly metabolized to fluoride and HFIP, which was rapidly glucuronidated and eliminated in the urine. The overall extent of sevoflurane metabolism was approximately 5%.
Articles
Evan D. Kharasch, MD, PhD, Andrew S. Armstrong, MBBS, FANZCA, Kerry Gunn, MBChB, FANZCA, Alan Artru, MD, Kathy Cox, BS, Michael D. Karol, PhD
Journal:
Anesthesiology
Anesthesiology. June 1995; 82(6):1379–1388.
Published: June 1995
Abstract
Background Sevoflurane is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Cytochrome P450 2E1 is the major isoform responsible for sevoflurane metabolism by human liver microsomes in vitro. This investigation tested the hypothesis that P450 2E1 is predominantly responsible for sevoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. Methods Twenty-one patients within 30% of ideal body weight, who provided institutional review board-approved informed consent and were randomized to receive disulfiram (500 mg oral, n = 11) or nothing (control, n = 10) the night before surgery, were evaluated. All patients received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction. Thereafter, sevoflurane was discontinued, and anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Blood sevoflurane concentrations during anesthesia and for 8 h thereafter were measured by gas chromatography. Plasma and urine fluoride and total (unconjugated plus glucuronidated) HFIP concentrations were measured by an ion-selective electrode and by gas chromatography, respectively, during anesthesia and for 96 h postoperatively. Results Patient groups were similar with respect to age, weight, sex, case duration, and intraoperative blood loss. The total sevoflurane dose, measured by cumulative end-tidal sevoflurane concentrations (3.7 +/- 0.1 MAC-h; mean +/- SE), total pulmonary uptake, and blood sevoflurane concentrations, was similar in both groups. In control patients, plasma fluoride and HFIP concentrations were increased compared to baseline values intraoperatively and postoperatively for the first 48 and 60 h, respectively. Disulfiram treatment significantly diminished this increase. Plasma fluoride concentrations increased from 2.1 +/- 0.3 microM (baseline) to 36.2 +/- 3.9 microM (peak) in control patients, but only from 1.7 +/- 0.2 to 17.0 +/- 1.6 microM in disulfiram-treated patients (P < 0.05 compared with control patients). Peak plasma HFIP concentrations were 39.8 +/- 2.6 and 14.4 +/- 1.1 microM in control and disulfiram-treated patients (P < 0.05), respectively. Areas under the plasma fluoride- and HFIP-time curves also were diminished significantly to 22% and 20% of control patients, respectively, by disulfiram treatment. Urinary excretion of fluoride and HFIP was similarly significantly diminished in disulfiram-treated patients. Cumulative 96-h fluoride and HFIP excretion in disulfiram-treated patient was 1,080 +/- 210 and 960 +/- 240 mumol, respectively, compared to 3,950 +/- 560 and 4,300 +/- 540 mumol in control patients (P < 0.05). Conclusions Disulfiram, an effective P450 2E1 inhibitor, substantially decreased fluoride ion and HFIP production during and after sevoflurane anesthesia. These results suggest that P450 2E1 is a predominant P450 isoform responsible for human sevoflurane metabolism in vivo.
Articles
Myron Vaster, M.D., Michael Bezman, M.D., David G. Nichols, M.D., Anne M. Lynn, M.D., Mark A. Helfaer, M.D., Jayant K. Deshpande, M.D., Paul N. Manson, M.D., Benjamin S. Carson, M.D., Lynne G. Maxwell, M.D., Joseph D. Tobias, M.D., Louise B. Grochow, M.D.
Journal:
Anesthesiology
Anesthesiology. October 1993; 79(4):733–738
Published: October 1993
Articles
Richard R. Bartkowski, M.D., Ph.D., Michael E. Goldberg, M.D., Suzanne Huffnagle, D.O., Richard H. Epstein, M.D
Journal:
Anesthesiology
Anesthesiology. February 1993; 78(2):260–265
Published: February 1993
Articles
Bernadette T. Veering, M.D., Anton G. L. Burm, Ph.D., Arie A. Vletter, B.Sc., Robert A. M. van den Hoeven, B.Sc., Johan Spierdijk, M.D., Ph.D., F.F.A.R.C.S. (Hon.)
Journal:
Anesthesiology
Anesthesiology. February 1991; 74(2):250–257
Published: February 1991
Articles
T C Krejcie, M.D., T K Henthorn, M.D., C A Shanks, M.D., A Asada, M.D., D A Kaozynski, B.S., M J Avram, Ph.D.
Journal:
Anesthesiology
Anesthesiology. September 1990; 73(3A):NA
Published: September 1990
Articles
J. F. Boylan, MB, S. A. Qureshi, PhD, S. Laganière, PhD, I. McGilveray, PhD, P. Hassard, BSc, G. O'Leary, MB, S. J. Teasdale, MD.
Journal:
Anesthesiology
Anesthesiology. September 1990; 73(3A):NA
Published: September 1990
Articles
C A Shanks, M.D., T K Henthorn, M.D., D A Kaozynski, B.S., A Asada, M.D., T C Krejoie, M.D., M J Avram, Ph.D
Journal:
Anesthesiology
Anesthesiology. September 1990; 73(3A):NA
Published: September 1990
Articles
Articles
W. J. Merrell, M.D., L. Gordon, M.B., Ch.B., F.F.A.R.C.S., A. J. J. Wood, M.B., Ch.B., F.R.C.P. (Edin), S. Shay, B.S., E. K. Jackson, Ph.D., M. Wood, M.B., Ch.B., F.F.A.R.C.S.
Journal:
Anesthesiology
Anesthesiology. February 1990; 72(2):308–314
Published: February 1990
Articles
Karin S. Khuenl-Brady, M.D., Manohar Sharma, Ph.D., Kyung Chung, M.D., Ronald D. Miller, M.D., Sandor Agoston, M.D., Ph.D., James E. Caldwell, F.F.R.A.C.S.
Journal:
Anesthesiology
Anesthesiology. December 1989; 71(6):919–922
Published: December 1989
Articles
Anton G. L. Burm, Ph.D., Jack W. Van Kleef, M.D., Ph.D., Nicolas P. E. Vermeulen, Ph.D., Geert Olthof, M.D., Douwe D. Breimer, Ph.D., Johan Spierdijk, M.D., Ph.D., F.F.A.R.C.S. (Hon.)
Journal:
Anesthesiology
Anesthesiology. October 1988; 69(4):584–592
Published: October 1988
Articles
HIROSHI OHNO, M.D., MAKOTO WATANABE, PH.D., JIRO SAITOH, M.D., YOSHINOBU SAEGUSA, B.S., YOKI HASEGAWA, M.D., TOSHIHIDE YONEZAWA, M.D.
Journal:
Anesthesiology
Anesthesiology. April 1988; 68(4):625–628
Published: April 1988
Articles
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