Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain

Hiraoka, Haruhiko; Yamamoto, Keiji; Miyoshi, Soutarou; Morita, Toshihiro; Nakamura, Katsunori; Kadoi, Yuuji; Kunimoto, Fumio; Horiuchi, Ryuya

doi:10.1111/j.1365-2125.2005.02393.x

Cited by 114 publications

(70 citation statements)

References 36 publications

(70 reference statements)

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“…Despite this potential importance, cutaneous drug metabolism is generally overlooked and rarely discussed during drug development. A better understanding of skin metabolism could also close the general in vitro-in vivo extrapolation gap for drugs where extensive extrahepatic metabolic clearance is suspected (Hiraoka et al, 2005;Gundert-Remy et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. This proof-of-concept study investigated phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model containing all skin cell types. Results show that skin explants have significant capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Novel skin metabolites were identified, including acyl glucuronides of indomethacin and diclofenac, glucuronides of 17b-estradiol, N-acetylprocainamide, and methoxy derivatives of 4-nitrocatechol and 2,3-dihydroxynaphthalene. Measured activities for 10 mM substrate incubations spanned a 1000-fold: from the highest 4.758 pmol·mg skin ·h -1 for 17b-estradiol 17-glucuronidation. Interindividual variability was 1.4-to 13.0-fold, the highest being 4-methylumbelliferone and diclofenac glucuronidation. Reaction rates were generally linear up to 4 hours, although 24-hour incubations enabled detection of metabolites in trace amounts. All reactions were unaffected by the inclusion of cosubstrates, and freezing of the fresh skin led to loss of glucuronidation activity. The predicted whole-skin intrinsic metabolic clearances were significantly lower compared with corresponding whole-liver intrinsic clearances, suggesting a relatively limited contribution of the skin to the body's total systemic phase II enzymemediated metabolic clearance. Nevertheless, the fresh full-thickness skin explants represent a suitable model to study cutaneous phase II metabolism not only in drug elimination but also in toxicity, as formation of acyl glucuronides and sulfate conjugates could play a role in skin adverse reactions.

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Section: Introductionmentioning

confidence: 99%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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“…Siteeffect studies have confirmed that venous sampling is equally representative of arterial drug concentrations, provided the infusion interval prior to sampling is longer than 20 min. [39][40][41][42][43][44] Second, the mathematical model described in this study is inherently susceptible to changes in the anesthetic maneuver and is incapable of predicting propofol concentrations in routine clinical practice or beyond the infusion rates used in our study. In the absence of controls that omit propofol anesthesia, we are unable to attribute either the magnitude or the pattern of hemodynamic changes to the administration of propofol.…”

Section: Discussionmentioning

confidence: 99%

Target-achieved propofol concentration during on-pump cardiac surgery: a pilot dose-finding study

Raedschelders

Laferlita

et al. 2009

Can J Anesth/J Can Anesth

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Purpose Propofol concentrations that produce laboratory-based cardioprotective effects are generally greater than those produced under routine anesthesia during cardiac surgery. It is unknown whether experimental cardioprotective propofol concentrations can routinely be achieved during cardiopulmonary bypass (CPB) using continuous infusion. Methods Twenty-four patients scheduled for primary aortocoronary bypass grafting with CPB were allocated to receive one of three propofol infusion rates; 50, 100, or 150 lg Á kg -1 Á min -1 in an open-label pilot study. Data were described using a line of best fit to derive an experimental clinical maneuver predicted to produce a whole blood concentration of 5 lg Á mL -1 at reperfusion. A predetermined interim analysis of 30 patients who were receiving the derived maneuver in an ongoing study was used to evaluate the maneuver. Cardiac index (CI), systemic vascular resistance index (SVRI), and left ventricular stroke work index (LVSWI) were recorded. Results The infusion rate-concentration curve had an equation of y = 0.215e 0.0279x , where y represents the whole blood concentration and x represents the infusion rate (r 2 = 0.781). The predicted infusion rate to achieve a mean concentration of 5 lg Á mL -1 was 113 lg Á kg -1 Á min -1 . The nearest practical rate is 120 lg Á kg -1 Á min -1 , producing a concentration of 5.39 (1.45) lg Á mL -1 . The values for CI, SVRI, and LVSWI were similar between groups at corresponding time periods. Conclusions An infusion rate of 120 lg Á kg -1 Á min -1 is clinically practical and capable of achieving experimental cardioprotective propofol concentrations at reperfusion. RésuméObjectif Les concentrations de propofol qui provoquent des effets cardioprotecteurs lors des tests de laboratoire sont en ge´ne´ral plus e´leve´es que celles produites sous une anesthe´sie de routine lors d'une chirurgie cardiaque. Nous ne savons pas si des concentrations expe´rimentales cardioprotectrices de propofol peuvent eˆtre atteintes de façon routinie`re pendant la circulation extracorporelle (CEC) avec une perfusion continue. Méthode Vingt-quatre patients devant subir un pontage aortocoronarien avec CEC ont e´te´randomise´s à recevoir l'un des trois vitesses de perfusion de propofol suivantes : 50, 100 ou 150 lgÁkg -1 Ámin -1 dans une e´tude pilote ouverte. Les donne´es ont e´te´de´crites a`l'aide d'une droite de re´gression afin de de´river une manoeuvre clinique expe´rimentale qui devrait produire une concentration de sang total de 5 lgÁmL -1 au moment de la reperfusion. Une

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“…Contradicting reports exist in the literature over the potential propofol metabolism and/or sequestration in the lung (Dawidowicz et al, 2000;He et al, 2000;Hiraoka et al, 2005;Takizawa et al, 2005a). Reduction in propofol concentration across the lung in one study was proportional to the formation of the quinol metabolite and assessment of the blood concentration data suggested a lung extraction ratio of 0.40 (Dawidowicz et al, 2000).…”

Section: Applying a Pbpk Model To Predict Renal Metabolism 745mentioning

confidence: 99%

Application of a Physiologically Based Pharmacokinetic Model to Assess Propofol Hepatic and Renal Glucuronidation in Isolation: Utility of In Vitro and In Vivo Data

Gill¹,

Gertz²,

Houston³

et al. 2013

Drug Metab Dispos

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A physiologically based pharmacokinetic (PBPK) modeling approach was used to assess the prediction accuracy of propofol hepatic and extrahepatic metabolic clearance and to address previously reported underprediction of in vivo clearance based on static in vitro-in vivo extrapolation methods. The predictive capacity of propofol intrinsic clearance data (CL int ) obtained in human hepatocytes and liver and kidney microsomes was assessed using the PBPK model developed in MATLAB software. Microsomal data obtained by both substrate depletion and metabolite formation methods and in the presence of 2% bovine serum albumin were considered in the analysis. Incorporation of hepatic and renal in vitro metabolic clearance in the PBPK model resulted in underprediction of propofol clearance regardless of the source of in vitro data; the predicted value did not exceed 35% of the observed clearance. Subsequently, propofol clinical data from three dose levels in intact patients and anhepatic subjects were used for the optimization of hepatic and renal CL int in a simultaneous fitting routine. Optimization process highlighted that renal glucuronidation clearance was underpredicted to a greater extent than liver clearance, requiring empirical scaling factors of 17 and 9, respectively. The use of optimized clearance parameters predicted hepatic and renal extraction ratios within 20% of the observed values, reported in an additional independent clinical study. This study highlights the complexity involved in assessing the contribution of extrahepatic clearance mechanisms and illustrates the application of PBPK modeling, in conjunction with clinical data, to assess prediction of clearance from in vitro data for each tissue individually.

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Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain

Cited by 114 publications

References 36 publications

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Target-achieved propofol concentration during on-pump cardiac surgery: a pilot dose-finding study

Application of a Physiologically Based Pharmacokinetic Model to Assess Propofol Hepatic and Renal Glucuronidation in Isolation: Utility of In Vitro and In Vivo Data

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