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From PubPKJump to: navigation, search IUPAC Name 8-chloro- 6-(2-fluorophenyl)- 1-methyl- 4H-imidazo[1,5-a] [1,4]benzodiazepine Physicochemical Properties CAS number 59467-70-8 PubChem 4192 DrugBank APRD00680 Molecular Formula C18H13ClFN3 Molecular Weight (g/mol) 325.767323 logP 2.68 H-Bond Donor 0 H-Bond Acceptor 4 Polar Surface Area (Å2) 30.2
Midazolam is a short-acting benzodiazepine widely used for preoperative sedation, induction, and maintenance of anesthesia.
- 1 Trade Names
- 2 In Vitro Metabolism & Transport
- 3 Pharmacokinetics
- 3.1 Summary of Pharmacokinetic Parameters
- 3.2 Pharmacokinetics in Preclinical Animals
- 3.3 Pharmacokinetics in Humans
- 3.4 Factors Influencing Pharmacokinetics
- 4 Drug Interactions
- 5 See also
- 6 External links
- 7 References
In Vitro Metabolism & Transport
MetabolismCYP Substrate Inhibitor Inducer UGT Substrate Inhibitor Inducer CYP1A1 UGT1A1 CYP1A2 UGT1A3 CYP1B1 UGT1A4 CYP2A6 UGT1A6 CYP2B6 UGT1A9 CYP2C8 UGT2A1 CYP2C9 UGT2A2 CYP2C19 UGT2A3 CYP2D6 UGT2B4 CYP2E1 UGT2B7 CYP2J2 UGT2B10 CYP3A4 Yes1 UGT2B11 CYP3A5 Yes1 UGT2B15 CYP3A7 UGT2B17
TransportABC Substrate Inhibitor Inducer SLC Substrate Inhibitor Inducer ABCB1 (MDR1) Yes1 SLC10A1 (NTCP) ABCB4 (MDR3) SLC10A2 (NTCP2) ABCB11 (BSEP) SLC15A1 (PEPT1) ABCC1 (MRP1) SLC15A2 (PEPT2) ABCC2 (MRP2) SLC16A1 (MCT1) ABCC3 (MRP3) SLC16A4 (MCT5) ABCC4 (MRP4) SLC22A1 (OCT1) ABCC5 (MRP5) SLC22A2 (OCT2) ABCC6 (MRP6) SLC22A3 (OCT3) ABCC10 (MRP7) SLC22A4 (OCTN1) ABCC11 (MRP8) SLC22A5 (OCTN2) ABCG2 (BCRP) SLC22A6 (OAT1) SLC22A7 (OAT2) SLC22A8 (OAT3) SLC22A9 (UST3) SLC22A11 (OAT4) SLC28A3 (CNT3) SLCO1A2 (OATP-A) SLCO1B1 (OATP-C) SLCO1B3 (OATP8) SLCO1C1 (OATP-F) SLCO2B1 (OATP-B) SLCO3A1 (OATP-D) SLCO4A1 (OATP-E) SLCO4C1 (OATP-H)
References: 1Tolle-Sander et al. 2003;
Summary of Pharmacokinetic ParametersCLiv: total plasma clearance after iv administration; CLR: renal clearance of drug from the plasma; Vss: volume of distribution at steady state; t1/2: elimination half-life; Foral: oral bioavailability; fa: fraction of administered dose absorbed; EG: gut extraction ratio; EH: hepatic extraction ratio; fu: unbound fraction of drug in plasma; b/p: blood-to-plasma ratio Mouse Rat Rabbit Dog Monkey Human CLiv (mL/min/kg) 4.99 ± 1.531 CLR (mL/min/kg) 0.055 Vss (L/kg) 0.669 ± 0.2521 t1/2β (h) 2.0 ± 0.51 Foral (%) 28.2 ± 9.41 fa 1 EG (%) 46.9 ± 19.781 EH (%) 44.4 ± 13.61 fu (%) 1.68 ± 0.372 b/p 0.533
References: 1 Tateishi et al. 2001 (n=20, healthy European American men); 2 Pentikainen et al. 1989; 3 Obach 1999; 4 Calvo 1992; 5Thummel et al. 1996.
Midazolam kineitcs were also reported by many other papers include: Allonen et al., 1981; Greenblatt et al. 1984; Klotz and Ziegler, 1982; Heizmann et al., 1983; Schwagmeier et al., 1998; Thummel et al. 1996; Wandel et al., 2000).
Additional reported values of midazolam unbound fraction in human plasama (fu) include: 3.41 ± 0.11 and 3.74 ± 0.11 for young male and female, respectively (Greenblatt et al. 1984); 1.92 ± 0.69 (Thummel et al. 1996).
Pharmacokinetics in Preclinical Animals
Pharmacokinetics in Humans
Midazolam has a short elimination half-life of around 2 hours. Oral bioavailability is low (around 30%) and is associated with considerable interindividual variability, resulted from extensive first-pass metabolism in both the gut and the liver.
Absorption of midazolam is complete and rapid, with peak plasma concentration being achieved at around 30 min after oral administration.
Midazolam is lipophic at physiological pH. It crosses the placenta and is distributed into breast milk (Matheson et al., 1990). Nitsun et al. (2006) reported that an average of 0.005% (range, 0.002%-0.013%) of the maternal midazolam dose excreted into milk within 24 hours of induction of anesthesia.
Extensive first-pass metabolism in both the gut and the liver (Tateishi et al. 2001), mediated by CYP3A.
Less than 1% of the administered midazolam was excreted in urine over 24 hours as unchanged drug (Thummel et al. 1996).
Factors Influencing Pharmacokinetics
Midazolam half-life can be prolonged in neonates and in elderly (Greenblatt et al. 1984; Albrecht et al., 1999).
No significant gender-related differences were noted in the systemic or oral clearance values (Thummel et al. 1996).
After intravenous injection plasma concentrations of midazolam were higher in Japanese subjects than those in European American men. This observation was associated with smaller initial and steady-state volumes of distribution in Japanese subjects. Normalization for body weight only modestly reduced these differences. The systemic clearance value of midazolam was 25% lower (in Japanese subjects, but this difference was not apparent after accounting for the smaller body weights of that group. No statistical differences were noted in the elimination half-life of midazolam between the two ethincity groups (Tateishi et al. 2001).
- Liver cirrhosis. The bioavoilability and AUC of oral midazolam were higher in liver cirrhosis patients than healthy volunteers (Pentikainen et al. 1989).
- Renal impairment. Unbound fraction in plasma increased in renal patient (Calvo et al. 1992). Five patients with severe renal impairment experienced prolonged sedation when given midazolam; this was attributed to accumulation of conjugated metabolites (Bauer et al., 1995).
- Obesity. Volume of distribution and half-life of midazolam increased significantly in obese volunteers compared to age and sex matched control subjects (Greenblatt et al. 1984).
to be updated
Significant changes in Cmax, tmax, and AUC were not found when midazolam was taken one hour before or with a meal as compared with the control condition. Significant changes in these parameters for both midazolam and its metabolite were seen when midazolam was ingested one hour after a meal: there was a delayed and reduced rate of absorption as well as a small reduction in the extent of absorption fa (Bornemann et al. 1986).
Effects on Other Drugs
Midazolam is not a known inhibitor of other drugs.
Effects by Other Drugs
Midazolam is exclusively metabolised by CYP3A. Drugs with potent CYP3A inhibitory properties can cause significant CYP3A-mediated drug-drug interactions.
- Anacetrapib Anacetrapib (single daily oral doses of 150 mg) did not affect the pharmacokinetics of oral midazolam (Krishna et al. 2009).
- Fluoxetine Fluoxetine (60mg per day) had no significant effect on the AUC of oral midazolam (Lam et al. 2003).
- Fluvoxamine Fluvoxamine (200 mg daily) increased the AUC of oral midazolam by 66% on average (Lam et al. 2003).
- Grapefruit juice
- Itraconazole Itraconazole (100 mg daily) increased the AUC of oral midazolam 6-fold, Cmax 2.5-fold and the elimination half-life 2-fold (Ahonen et al. 1995).
- Ketoconazole Ketoconazole (200 mg once daily) increased the AUC of oral midazolam by 772% on average (Lam et al. 2003). In another study, ketoconazole (200 mg daily) increased the AUC of midazolam to 5-fold after intravenous midazolam administration and to 16-fold after oral midazolam administration (Tsunoda et al. 1999).
- Nefazodone Nefazodone (400 mg once daily) increased the AUC of oral midazolam by 444% on average (Lam et al. 2003).
- Rifampicin Rifampicin (600 mg once daily) significantly increased the systemic and oral clearance of midazolam (Gorski et al. 2004).
- Saquinavir In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers received oral doses of either 1200 mg saquinavir or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Saquinavir increased the bioavailability of oral midazolam from 41% to 90%, Cmax more than twofold, and the AUC more than fivefold. Saquinavir decreased the clearance of intravenous midazolam by 56% and increased its elimination half-life from 4.1 to 9.5 hours (Palkama et al. 1999).
- Terbinafine Terbinafine (250 mg daily) did not significantly affect the pharmacokinetics of midazolam (Ahonen et al. 1995).
- Voriconazole In a randomized, crossover study, ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Voriconazole reduced the clearance of intravenous midazolam by 72% and increased its elimination half-life from 2.8 to 8.3 hours. The peak concentration and the area under the plasma concentration-time curve of oral midazolam were increased by 3.8- and 10.3-fold, respectively. The oral bioavailability of midazolam was increased from 31% to 84%. (Saari et al. 2006).
- Ahonen J, Olkkola KT and Neuvonen PJ (1995) Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers Br J Clin Pharmacol 40:270-272.
- Allonen H, Ziegler G and Klotz U (1981) Midazolam Kinetics Clin Pharmacol Ther 30:653-661.
- Bauer TM, Ritz R, Haberthur C, Ha HR, Hunkeler W, Sleight AJ, Scollo-Lavizzari G and Haefeli WE (1995) Prolonged sedation due to accumulation of conjugated metabolites of midazolam Lancet 346:145-147.
- Bornemann LD, Crews T, Chen SS, Twardak S and Patel IH (1986) Influence of food on midazolam absorption J Clin Pharmacol 26:55-59.
- Calvo R, Suarez E, Rodriguez-Sasiain JM and Martinez I (1992) The influence of renal failure on the kinetics of intravenous midazolam: an in vitro and in vivo study Res Commun Chem Pathol Pharmacol 78:311-320.
- Gorski JC, Vannaprasaht S, Hamman MA, Ambrosius WT, Bruce MA, Haehner-Daniels B and Hall SD (2003) The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity Clin Pharmacol Ther 74:275-287.
- Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA and Shader RI (1984) Effect of age, gender, and obesity on midazolam kinetics Anesthesiology 61:27-35.
- Heizmann P, Eckert M and Ziegler WH (1983) Pharmacokinetics and bioavailability of midazolam in man Br J Clin Pharmacol 16:S43-S49.
- Klotz U and Ziegler G (1982) Physiologic and temporal variation in hepatic elimination of midazolam Clin Pharmacol Ther 32:107-112.
- Krishna R, Bergman AJ, Jin B, Garg A, Roadcap B, Chiou R, Dru J, Cote J, Laethem T, Wang RW, Didolkar V, Vets E, Gottesdiener K and Wagner JA (2009) Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers J Clin Pharmacol 49:80-87.
- Lam YWF, Alfaro CL, Ereshefsky L and Miller M (2003) Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone J Clin Pharmacol 43:1274-1282.
- Matheson I, Lunde PK and Bredesen JE (1990) Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects Br J Clin Pharmacol 30:787-793.
- Nitsun M, Szokol JW, Saleh HJ, Murphy GS, Vender JS, Luong L, Raikoff K and Avram MJ (2006) Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk Clin Pharmacol Ther 79:549-557.
- Obach RS (1999) Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes Drug Metab Dispos 27:1350-1359.
- Palkama VJ, Ahonen J, Neuvonen PJ, Olkkola KT (1999) Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam Clin Pharmacol Ther 66:33-9.
- Pentikainen PJ, Valisalmi L, Himberg JJ and Crevoisier C (1989) Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects J Clin Pharmacol 29:272-277.
- Saari TI, Laine K, Leino K, Valtonen M, Neuvonen PJ, Olkkola KT (2006) Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam Clin Pharmacol Ther 79:362-70.
- Schwagmeier R, Alincic S and Striebel HW (1998) Midazolam pharmacokinetics following intravenous and buccal administration Br J Clin Pharmacol 46:203-206.
- Smith MT, Eadie MJ, Brophy TO (1981) The pharmacokinetics of midazolam in man Eur J Clin Pharmacol 19:271-278.
- Tateishi T, Watanabe M, Nakura H, Asoh M, Shirai H, Mizorogi Y, Kobayashi S, Thummel KE and Wilkinson GR (2001) CYP3A activity in European American and Japanese men using midazolam as an in vivo probe Clin Pharmacol Ther 69:333-339.
- Thummel KE, Oshea D, Paine MF, Shen DD, Kunze KL, Perkins JD and Wilkinson GR (1996) Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism Clin Pharmacol Ther 59:491-502.
- Tolle-Sander S, Rautio J, Wring S, Polli JW, Polli JE (2003) Midazolam exhibits characteristics of a highly permeable P-glycoprotein substrate Pharm Res 20:757-64.
- Tsunoda SM, Velez RL, von Moltke LL and Greenblatt DJ (1999) Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole Clin Pharmacol Ther 66:461-471.
- Wandel C, Witte JS, Hall JM, Stein CM, Wood AJJ and Wilkinson GR (2000) CYP3A activity in African American and European American men: Population differences and functional effect of the CYP3A4*1B 5 '-promoter region polymorphism Clin Pharmacol Ther 68:82-91.
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