Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol

References

• De Lima L. International Association for Hospice and Palliative Care list of essential medicines for palliative care. Ann Oncol. 2007 Feb;18(2):395–399.
   PubMed Web of Science ®Google Scholar
• Cheeti S, Budha NR, Rajan S, et al. A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer. Biopharm Drug Dispos. 2013 Apr;34(3):141–154.
   PubMed Web of Science ®Google Scholar
• Stevenson J, Abernethy AP, Miller C, et al. Managing comorbidities in patients at the end of life. BMJ. 2004 Oct 16;329(7471):909–912.
   PubMed Web of Science ®Google Scholar
• Bruera E, Hui D. Palliative care research: lessons learned by our team over the last 25 years. Palliat Med. 2013 Dec;27(10):939–951.
   PubMed Web of Science ®Google Scholar
• Sarhill N, Walsh D, Nelson K, et al. Evaluation and treatment of cancer-related fluid deficits: volume depletion and dehydration. Support Care Cancer. 2001 Sep;9(6):408–419.
   PubMed Web of Science ®Google Scholar
• Masman AD, van Dijk M, Tibboel D, et al. Medication use during end-of-life care in a palliative care centre. Int J Clin Pharm. 2015 Oct;37(5):767–775.
   PubMed Web of Science ®Google Scholar
• Reuben DB, Mor V, Hiris J. Clinical symptoms and length of survival in patients with terminal cancer. Arch Intern Med. 1988 Jul;148(7):1586–1591.
   PubMed Web of Science ®Google Scholar
• Van Lancker A, Velghe A, Van Hecke A, et al. Prevalence of symptoms in older cancer patients receiving palliative care: a systematic review and meta-analysis. J Pain Symptom Manage. 2014 Jan;47(1):90–104.
   PubMed Web of Science ®Google Scholar
• Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003 Aug;38(8):843–853.
   PubMed Web of Science ®Google Scholar
• Lichtman SM. Guidelines for the treatment of elderly cancer patients. Cancer Control. 2003;10(6):445–453.
   PubMedGoogle Scholar
• Smith BS, Yogaratnam D, Levasseur-Franklin KE, et al. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012 May;141(5):1327–1336.
   PubMed Web of Science ®Google Scholar
• Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr. 2006 Apr;83(4):735–743.
   PubMed Web of Science ®Google Scholar
• Trobec K, Kerec Kos M, von Haehling S, et al. Pharmacokinetics of drugs in cachectic patients: a systematic review. PLoS One. 2013;8(11):e79603.
   PubMed Web of Science ®Google Scholar
• Mihelic RA. Pharmacology of palliative medicine. Semin Oncol Nurs. 2005 Feb;21(1):29–35.
   PubMedGoogle Scholar
• Smucker D, Wang R. The effect of aging on digestive processes. In: Masoro EJ, editor. CRC handbook of physiology in aging. Boca Raton (FL): CRC Press; 1981. p. 235–285.
   Google Scholar
• Chang SF, Moore L, Chien YW. Pharmacokinetics and bioavailability of hydromorphone: effect of various routes of administration. Pharm Res. 1988 Nov;5(11):718–721.
   PubMed Web of Science ®Google Scholar
• Sarhill N, Mahmoud FA, Christie R, et al. Assessment of nutritional status and fluid deficits in advanced cancer. Am J Hosp Palliat Care. 2003 Nov–Dec;20(6):465–473.
   PubMedGoogle Scholar
• Krishnan V, Murray P. Pharmacologic issues in the critically ill. Clin Chest Med. 2003 Dec;24(4):671–688.
   PubMed Web of Science ®Google Scholar
• Viganò A, Dorgan M, Buckingham J, et al. Survival prediction in terminal cancer patients: a systematic review of the medical literature. Palliat Med. 2000 Sep;14(5):363–374.
   PubMed Web of Science ®Google Scholar
• Tisdale MJ. Molecular pathways leading to cancer cachexia. Physiology. 2005 Oct;20:340–348.
   PubMed Web of Science ®Google Scholar
• Fearon KC, Preston T. Body composition in cancer cachexia. Infusionstherapie. 1990 Apr;17(Suppl 3):63–66.
   PubMed Web of Science ®Google Scholar
• Pichard C, Kyle UG. Body composition measurements during wasting diseases. Curr Opin Clin Nutr Metab Care. 1998 Jul;1(4):357–361.
   PubMedGoogle Scholar
• Muscaritoli M, Anker SD, Argilés J, et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) ‘cachexia-anorexia in chronic wasting diseases’ and ‘nutrition in geriatrics’. Clin Nut. 2010 Apr;29(2):154–159.
   PubMed Web of Science ®Google Scholar
• Verhagen CAHHVM. Pathofysiologie, symptomen en problematiek rond de terminale patiënt. In: van Bommel EMG, Tukker J, editors. 26e Anselmus Colloquium De laatste fase. Stichting Organisatie Anselmus Colloquium, Houten, 2014 Sept 18, Utrecht; 2014.
   Google Scholar
• Mahmoud FA, Rivera NI. The role of C-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep. 2002 May;4(3):250–255.
   PubMedGoogle Scholar
• Lindenmann J, Fink-Neuboeck N, Koesslbacher M, et al. The influence of elevated levels of C-reactive protein and hypoalbuminemia on survival in patients with advanced inoperable esophageal cancer undergoing palliative treatment. J Surg Oncol. 2014 Nov;110(6):645–650.
   PubMed Web of Science ®Google Scholar
• Slaviero KA, Clarke SJ, Rivory LP. Inflammatory response: an unrecognised source of variability in the pharmacokinetics and pharmacodynamics of cancer chemotherapy. Lancet Oncol. 2003;4:224–232.
   PubMed Web of Science ®Google Scholar
• Evans WJ, Morley JE, Argilés J, et al. Cachexia: a new definition. Clin Nut. 2008 Dec;27(6):793–799.
   PubMed Web of Science ®Google Scholar
• Kemik O, Sumer A, Kemik AS, et al. The relationship among acute-phase response proteins, cytokines and hormones in cachectic patients with colon cancer. World J Surg Oncol. 2010;8:85.
   PubMed Web of Science ®Google Scholar
• Araújo JP, Lourenço P, Rocha-Gonçalves F, et al. Nutritional markers and prognosis in cardiac cachexia. Int J Cardiol. 2011 Feb 3;146(3):359–363.
   PubMed Web of Science ®Google Scholar
• Woo J, Chan HS, Or KH, et al. Effect of age and disease on two drug binding proteins: albumin and alpha-1- acid glycoprotein. Clin Biochem. 1994 Aug;27(4):289–292.
   PubMed Web of Science ®Google Scholar
• Piafsky KM. Disease-induced changes in the plasma binding of basic drugs. Clin Pharmacokinet. 1980 May–Jun;5(3):246–262.
   PubMed Web of Science ®Google Scholar
• Duché JC, Urien S, Simon N, et al. Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer. Clin Biochem. 2000 Apr;33(3):197–202.
   PubMed Web of Science ®Google Scholar
• Israili ZH, Dayton PG. Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev. 2001 May;33(2):161–235.
   PubMed Web of Science ®Google Scholar
• Delcò F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529–545.
   PubMed Web of Science ®Google Scholar
• Alvarez AM, Mukherjee D. Liver abnormalities in cardiac diseases and heart failure. Int J Angiol. 2011 Sep;20(3):135–142.
   PubMedGoogle Scholar
• Mapel D. Renal and hepatobiliary dysfunction in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2014 Mar;20(2):186–193.
   PubMed Web of Science ®Google Scholar
• Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet. 1995 Nov;29(5):370–391.
   PubMed Web of Science ®Google Scholar
• Raiten DJ. Nutrition, pharmacology, and toxicology: a dialectic. In: Massaro E, editor. Handbook of human toxicology. Boca Raton (FL): CRC Press; 1997.
   Google Scholar
• George J, Byth K, Farrell GC. Influence of clinicopathological variables on CYP protein expression in human liver. J Gastroenterol Hepatol. 1996 Jan;11(1):33–39.
   PubMed Web of Science ®Google Scholar
• Naito T, Tashiro M, Yamamoto K, et al. Impact of cachexia on pharmacokinetic disposition of and clinical responses to oxycodone in cancer patients. Eur J Clin Pharmacol. 2012 Oct;68(10):1411–1418.
   PubMed Web of Science ®Google Scholar
• Chen YL, Le Vraux V, Leneveu A, et al. Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics. Clin Pharmacol Ther. 1994 Jun;55(6):649–660.
   PubMed Web of Science ®Google Scholar
• Williams ML, Bhargava P, Cherrouk I, et al. A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer. Br J Clin Pharmacol. 2000 May;49(5):485–488.
   PubMed Web of Science ®Google Scholar
• Rivory LP, Slaviero KA, Clarke SJ. Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response. Br J Cancer. 2002 Jul 29;87(3):277–280.
   PubMed Web of Science ®Google Scholar
• Yamaguchi A, Tateishi T, Okano Y, et al. Higher incidence of elevated body temperature or increased C-reactive protein level in asthmatic children showing transient reduction of theophylline metabolism. J Clin Pharmacol. 2000 Mar;40(3):284–289.
   PubMed Web of Science ®Google Scholar
• Frye RF, Schneider VM, Frye CS, et al. Plasma levels of TNF-alpha and IL-6 are inversely related to cytochrome P450-dependent drug metabolism in patients with congestive heart failure. J Card Fail. 2002 Oct;8(5):315–319.
   PubMed Web of Science ®Google Scholar
• Islam M, Frye RF, Richards TJ, et al. Differential effect of IFNalpha-2b on the cytochrome P450 enzyme system: a potential basis of IFN toxicity and its modulation by other drugs. Clin Cancer Res. 2002 Aug;8(8):2480–2487.
   PubMed Web of Science ®Google Scholar
• Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol. 1976 Mar;31(2):155–163.
   PubMedGoogle Scholar
• Launay-Vacher V, Oudard S, Janus N, et al. Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study. Cancer. 2007 Sep 15;110(6):1376–1384.
   PubMed Web of Science ®Google Scholar
• WHO. Essential medicines in palliative care: executive summary. WHO Press, Geneva. 2013.
   Google Scholar
• Olsen GD. Morphine binding to human plasma proteins. Clin Pharmacol Ther. 1975 Jan;17(1):31–35.
   PubMed Web of Science ®Google Scholar
• Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet. 1998 May;34(5):359–373.
   PubMed Web of Science ®Google Scholar
• Lötsch J, Stockmann A, Kobal G, et al. Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers. Clin Pharmacol Ther. 1996 Sep;60(3):316–325.
   PubMed Web of Science ®Google Scholar
• Christrup LL. Morphine metabolites. Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 2):116–122.
   PubMed Web of Science ®Google Scholar
• Donnelly S, Davis MP, Walsh D, et al. Morphine in cancer pain management: a practical guide. Supportive Care Cancer. 2002;10(1):13–35.
   PubMed Web of Science ®Google Scholar
• Glare PA, Walsh TD. Clinical pharmacokinetics of morphine. Ther Drug Monit. 1991 Jan;13(1):1–23.
   PubMed Web of Science ®Google Scholar
• Francés B, Gout R, Campistron G, et al. Morphine-6-glucuronide is more mu-selective and potent in analgesic tests than morphine. Prog Clin Biol Res. 1990;328:477–480.
   PubMedGoogle Scholar
• Pasternak GW, Bodnar RJ, Clark JA, et al. Morphine-6-glucuronide, a potent mu agonist. Life Sci. 1987 Dec 28;41(26):2845–2849.
   PubMed Web of Science ®Google Scholar
• Paul D, Standifer KM, Inturrisi CE, et al. Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther. 1989 Nov;251(2):477–483.
   PubMed Web of Science ®Google Scholar
• Klimas R, Mikus G. Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth. 2014 Jul 1;113:935–944.
   PubMed Web of Science ®Google Scholar
• Wu D, Kang YS, Bickel U, et al. Blood-brain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Metab Dispos. 1997 Jun;25(6):768–771.
   PubMed Web of Science ®Google Scholar
• Janicki PK, Erskine WA, James MF. The route of prolonged morphine administration affects the pattern of its metabolites in the urine of chronically treated patients. Eur J Clin Chem Clin Biochem. 1991 Jun;29(6):391–393.
   PubMedGoogle Scholar
• Portenoy RK, Thaler HT, Inturrisi CE, et al. The metabolite morphine-6-glucuronide contributes to the analgesia produced by morphine infusion in patients with pain and normal renal function. Clin Pharmacol Ther. 1992 Apr;51(4):422–431.
   PubMed Web of Science ®Google Scholar
• Bartlett SE, Dodd PR, Smith MT. Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites. Pharmacol Toxicol. 1994 Aug;75(2):73–81.
   PubMedGoogle Scholar
• Löser SV, Meyer J, Freudenthaler S, et al. Morphine-6-O-beta-D-glucuronide but not morphine-3-O-beta-D-glucuronide binds to mu-, delta- and kappa- specific opioid binding sites in cerebral membranes. Naunyn Schmiedebergs Arch Pharmacol. 1996 Jul;354(2):192–197.
   PubMed Web of Science ®Google Scholar
• Chen ZR, Irvine RJ, Somogyi AA, et al. Mu receptor binding of some commonly used opioids and their metabolites. Life Sci. 1991;48(22):2165–2171.
   PubMed Web of Science ®Google Scholar
• Penson RT, Joel SP, Bakhshi K, et al. Randomized placebo-controlled trial of the activity of the morphine glucuronides. Clin Pharmacol Ther. 2000 Dec;68(6):667–676.
   PubMed Web of Science ®Google Scholar
• Lewis SS, Hutchinson MR, Rezvani N, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience. 2010 Jan 20;165(2):569–583.
   PubMed Web of Science ®Google Scholar
• Baillie SP, Bateman DN, Coates PE, et al. Age and the pharmacokinetics of morphine. Age Ageing. 1989;18:258–262.
   PubMed Web of Science ®Google Scholar
• Säwe J, Dahlström B, Paalzow L, et al. Morphine kinetics in cancer patients. Clin Pharmacol Ther. 1981 Nov;30(5):629–635.
   PubMed Web of Science ®Google Scholar
• Säwe J, Kager L, Svensson Eng JO, et al. Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation. Br J Clin Pharmacol. 1985 Apr;19(4):495–501.
   PubMed Web of Science ®Google Scholar
• Faura CC, Collins SL, Moore RA, et al. Systematic review of factors affecting the ratios of morphine and its major metabolites. Pain. 1998 Jan;74(1):43–53.
   PubMed Web of Science ®Google Scholar
• Klepstad P, Dale O, Kaasa S, et al. Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand. 2003 Jul;47(6):725–731.
   PubMed Web of Science ®Google Scholar
• Osborne R, Joel S, Trew D, et al. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther. 1990 Jan;47(1):12–19.
   PubMed Web of Science ®Google Scholar
• Peterson GM, Randall CT, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol. 1990;38(2):121–124.
   PubMed Web of Science ®Google Scholar
• Osborne R, Joel S, Grebenik K, et al. The pharmacokinetics of morphine and morphine glucuronides in kidney failure. Clin Pharmacol Ther. 1993 Aug;54(2):158–167.
   PubMed Web of Science ®Google Scholar
• D’Honneur G, Gilton A, Sandouk P, et al. Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology. 1994 Jul;81(1):87–93.
   PubMed Web of Science ®Google Scholar
• Chan GL, Matzke GR. Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics. Drug Intell Clin Pharm. 1987 Oct;21(10):773–783.
   PubMedGoogle Scholar
• Regnard CF, Twycross RG. Metabolism of narcotics. BMJ. 1984 Mar 17;288(6420):860.
   PubMed Web of Science ®Google Scholar
• Hoskin PJ, Hanks GW. The management of symptoms in advanced cancer: experience in a hospital-based continuing care unit. J R Soc Med. 1988 Jun;81(6):341–344.
   PubMed Web of Science ®Google Scholar
• Thompson PI, Joel SP, John L, et al. Respiratory depression following morphine and morphine-6-glucuronide in normal subjects. Br J Clin Pharmacol. 1995 Aug;40(2):145–152.
   PubMed Web of Science ®Google Scholar
• Peat SJ, Hanna MH, Woodham M, et al. Morphine-6-glucuronide: effects on ventilation in normal volunteers. Pain. 1991 Apr;45(1):101–104.
   PubMed Web of Science ®Google Scholar
• Romberg R, Olofsen E, Sarton E, et al. Pharmacodynamic effect of morphine-6-glucuronide versus morphine on hypoxic and hypercapnic breathing in healthy volunteers. Anesthesiology. 2003;99(4):788–798.
   PubMed Web of Science ®Google Scholar
• Morita T, Tei Y, Tsunoda J, et al. Increased plasma morphine metabolites in terminally ill cancer patients with delirium: an intra-individual comparison. J Pain Symptom Manage. 2002;23(2):107–113.
   PubMed Web of Science ®Google Scholar
• Sawe J. Morphine and its 3- and 6-glucuronides in plasma and urine during chronic oral administration in cancer patients. In: Foley KM, Lnturrisi CE, editors. Advances in pain research and therapy. New York (NY): Raven Press; 1986. p. 45–55.
   Google Scholar
• Sjøgren P, Jonsson T, Jensen NH, et al. Hyperalgesia and myoclonus in terminal cancer patients treated with continuous intravenous morphine. Pain. 1993;55(1):93–97.
   PubMed Web of Science ®Google Scholar
• Gretton SK, Ross JR, Rutter D, et al. Plasma morphine and metabolite concentrations are associated with clinical effects of morphine in cancer patients. J Pain Symptom Manage. 2013;45(4):670–680.
   PubMed Web of Science ®Google Scholar
• Ferris DJ. Controlling myoclonus after high-dosage morphine infusions. Am J Health Syst Pharm. 1999 May 15;56(10):1009–1010.
   PubMed Web of Science ®Google Scholar
• Smith MT, Wright AW, Williams BE, et al. Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain management. Anesth Analg. 1999 Jan;88(1):109–116.
   PubMed Web of Science ®Google Scholar
• McCann S, Yaksh TL, Von Gunten CF. Correlation between myoclonus and the 3-glucuronide metabolites in patients treated with morphine or hydromorphone: a pilot study. J Opioid Manage. 2010;6(2):87–94.
   PubMedGoogle Scholar
• Oosten AW, Oldenmenger WH, van Zuylen C, et al. Higher doses of opioids in patients who need palliative sedation prior to death: cause or consequence? Eur J Cancer. 2011 Oct;47(15):2341–2346.
   PubMed Web of Science ®Google Scholar
• Cherny NI. Sedation for the care of patients with advanced cancer. Nat Clin Pract Oncol. 2006;3(9):492–500.
   PubMedGoogle Scholar
• Farriols C, Ferrández O, Planas J, et al. Changes in the prescription of psychotropic drugs in the palliative care of advanced cancer patients over a seven-year period. J Pain Symptom Manage. 2012 May;43(5):945–952.
   PubMed Web of Science ®Google Scholar
• Cherny NI, Grp EGW. ESMO Clinical Practice Guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation. Ann Oncol. 2014 Sep;25:143–152.
   PubMed Web of Science ®Google Scholar
• Jamei M, Turner D, Yang J, et al. Population-based mechanistic prediction of oral drug absorption. AAPS J. 2009 Jun;11(2):225–237.
   PubMed Web of Science ®Google Scholar
• Brill MJ, van Rongen A, Houwink AP, et al. Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers. Clin Pharmacokinet. 2014 Oct;53(10):931–941.
   PubMed Web of Science ®Google Scholar
• Reves JG, Fragen RJ, Vinik HR, et al. Midazolam: pharmacology and uses. Anesthesiology. 1985 Mar;62(3):310–324.
   PubMed Web of Science ®Google Scholar
• Moschitto LJ, Greenblatt DJ. Concentration-independent plasma protein binding of benzodiazepines. J Pharm Pharmacol. 1983 Mar;35(3):179–180.
   PubMed Web of Science ®Google Scholar
• Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy. 1985 May–Jun;5(3):138–155.
   PubMed Web of Science ®Google Scholar
• Maitre PO, Funk B, Crevoisier C, et al. Pharmacokinetics of midazolam in patients recovering from cardiac surgery. Eur J Clin Pharmacol. 1989;37(2):161–166.
   PubMed Web of Science ®Google Scholar
• Malacrida R, Fritz ME, Suter PM, et al. Pharmacokinetics of midazolam administered by continuous intravenous infusion to intensive care patients. Crit Care Med. 1992 Aug;20(8):1123–1126.
   PubMed Web of Science ®Google Scholar
• Greenblatt DJ, Abernethy DR, Locniskar A, et al. Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology. 1984 Jul;61(1):27–35.
   PubMed Web of Science ®Google Scholar
• Brill MJ, van Rongen A, van Dongen EP, et al. The pharmacokinetics of the CYP3A substrate midazolam in morbidly obese patients before and one year after bariatric surgery. Pharm Res. 2015 Jul 23;32:3927–3936.
   PubMed Web of Science ®Google Scholar
• van Rongen A, Vaughns JD, Moorthy G, et al. Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents. Br J Clin Pharmacol. 2015 Jun 4;80:1185–1196.
   PubMed Web of Science ®Google Scholar
• Halliday NJ, Dundee JW, Collier PS, et al. Influence of plasma proteins on the onset of hypnotic action of intravenous midazolam. Anaesthesia. 1985 Aug;40(8):763–766.
   PubMed Web of Science ®Google Scholar
• Cvan Trobec K, Kerec Kos M, Trontelj J, et al. Influence of cancer cachexia on drug liver metabolism and renal elimination in rats. J Cachexia Sarcopenia Muscle. 2015 Mar;6(1):45–52.
   PubMed Web of Science ®Google Scholar
• Albarmawi A, Czock D, Gauss A, et al. CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores. Br J Clin Pharmacol. 2014;77(1):160–169.
   PubMed Web of Science ®Google Scholar
• Bleasel MD, Peterson GM, Dunne PF. Plasma concentrations of midazolam during continuous subcutaneous administration in palliative care. Palliat Med. 1994;8(3):231–236.
   PubMedGoogle Scholar
• Matsunaga T, Maruyama M, Matsubara T, et al. Mechanisms of CYP3A induction by glucocorticoids in human fetal liver cells. Drug Metab Pharmacokinet. 2012;27(6):653–657.
   PubMed Web of Science ®Google Scholar
• McCune JS, Hawke RL, LeCluyse EL, et al. In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone. Clin Pharmacol Ther. 2000 Oct;68(4):356–366.
   PubMed Web of Science ®Google Scholar
• Bauer TM, Ritz R, Haberthür C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995 Jul 15;346(8968):145–147.
   PubMed Web of Science ®Google Scholar
• Prommer E. Role of haloperidol in palliative medicine: an update. Am J Hosp Palliat Care. 2012 Jun;29(4):295–301.
   PubMed Web of Science ®Google Scholar
• Bartz L, Klein C, Seifert A, et al. Subcutaneous administration of drugs in palliative care: results of a systematic observational study. J Pain Symptom Manage. 2014 Apr 21;48:540–547.
   PubMed Web of Science ®Google Scholar
• Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet. 1999 Dec;37(6):435–456.
   PubMed Web of Science ®Google Scholar
• Nishimuta H, Nakagawa T, Nomura N, et al. Significance of reductive metabolism in human intestine and quantitative prediction of intestinal first-pass metabolism by cytosolic reductive enzymes. Drug Metab Dispos. 2013 May;41(5):1104–1111.
   PubMed Web of Science ®Google Scholar
• Forsman A, Ohman R. Studies on serum protein binding of haloperidol. Curr Ther Res Clin Exp. 1977 Feb;21(2):245–255.
   PubMed Web of Science ®Google Scholar
• Rowell FJ, Hui SM, Fairbairn AF, et al. Total and free serum haloperidol levels in schizophrenic patients and the effect of age thioridazine and fatty acid on haloperidol-serum protein binding in vitro. Br J Clin Pharmacol. 1981 Apr;11(4):377–382.
   PubMed Web of Science ®Google Scholar
• Someya T, Shibasaki M, Noguchi T, et al. Haloperidol metabolism in psychiatric patients: importance of glucuronidation and carbonyl reduction. J Clin Psychopharmacol. 1992 Jun;12(3):169–174.
   PubMed Web of Science ®Google Scholar
• Fang J, Baker GB, Silverstone PH, et al. Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol. 1997 Apr;17(2):227–233.
   PubMed Web of Science ®Google Scholar
• Midha KK, Hawes EM, Hubbard JW, et al. Interconversion between haloperidol and reduced haloperidol in humans. J Clin Psychopharmacol. 1987 Oct;7(5):362–364.
   PubMed Web of Science ®Google Scholar
• Chakraborty BS, Hubbard JW, Hawes EM, et al. Interconversion between haloperidol and reduced haloperidol in healthy volunteers. Eur J Clin Pharmacol. 1989;37(1):45–48.
   PubMed Web of Science ®Google Scholar
• Jann MW, Lam YW, Chang WH. Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients. Psychopharmacology (Berl). 1990;101(1):107–111.
   PubMed Web of Science ®Google Scholar
• Kudo S, Odomi M. Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation. Eur J Clin Pharmacol. 1998 May;54(3):253–259.
   PubMed Web of Science ®Google Scholar
• Pan LP, De Vriendt C, Belpaire FM. In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol. Pharmacogenetics. 1998 Oct;8(5):383–389.
   PubMedGoogle Scholar
• Johnson PC Jr, Charalampous KD, Braun GA. Absorption and excretion of tritiated haloperidol in man. (A preliminary report). Int J Neuropsychiatry. 1967 Aug;3(Suppl 1):24–25.
   PubMedGoogle Scholar
• Anderson RJ, Gambertoglio JG, Schrier RW. Clinical use of drugs in renal failure. Springfield (IL): Thomas; 1976.
   Google Scholar
• Forsman AO. Individual variability in response to haloperidol. Proc R Soc Med. 1976;69(suppl 1):9–12.
   PubMedGoogle Scholar
• Jann MW, Ereshefsky L, Saklad SR, et al. Effects of carbamazepine on plasma haloperidol levels. J Clin Psychopharmacol. 1985 Apr;5(2):106–109.
   PubMed Web of Science ®Google Scholar
• Kidron R, Averbuch I, Klein E, et al. Carbamazepine-induced reduction of blood levels of haloperidol in chronic schizophrenia. Biol Psychiatry. 1985 Feb;20(2):219–222.
   PubMed Web of Science ®Google Scholar
• Arana GW, Goff DC, Friedman H, et al. Does carbamazepine-induced reduction of plasma haloperidol levels worsen psychotic symptoms? Am J Psychiatry. 1986 May;143(5):650–651.
   PubMed Web of Science ®Google Scholar
• Hesslinger B, Normann C, Langosch JM, et al. Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. J Clin Psychopharmacol. 1999 Aug;19(4):310–315.
   PubMed Web of Science ®Google Scholar
• Mihara K, Suzuki A, Kondo T, et al. Effects of the CYP2D6*10 allele on the steady-state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. Clin Pharmacol Ther. 1999 Mar;65(3):291–294.
   PubMed Web of Science ®Google Scholar
• Goff DC, Midha KK, Brotman AW, et al. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine. Am J Psychiatry. 1991 Jun;148(6):790–792.
   PubMed Web of Science ®Google Scholar
• Viala A, Aymard N, Leyris A, et al. [Pharmaco-clinical correlations during fluoxetine administration in patients with depressive schizophrenia treated with haloperidol decanoate]. Therapie. 1996 Jan–Feb;51(1):19–25. French.
   PubMed Web of Science ®Google Scholar
• Goff DC, Midha KK, Sarid-Segal O, et al. A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology (Berl). 1995 Feb;117(4):417–423.
   PubMed Web of Science ®Google Scholar
• Avenoso A, Spinà E, Campo G, et al. Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications. Pharmacol Res. 1997 Apr;35(4):335–339.
   PubMed Web of Science ®Google Scholar
• Gysels MH, Evans C, Higginson IJ. Patient, caregiver, health professional and researcher views and experiences of participating in research at the end of life: a critical interpretive synthesis of the literature. BMC Med Res Methodol. 2012;12:123.
   PubMed Web of Science ®Google Scholar
• Ohde S, Hayashi A, Takahasi O, et al. A 2-week prognostic prediction model for terminal cancer patients in a palliative care unit at a Japanese general hospital. Palliat Med. 2011 Mar;25(2):170–176.
   PubMed Web of Science ®Google Scholar