Pharmacokinetics of midazolam in the aged

Smith, Maree T.; Heazlewood, V.; Eadie, M. J.; Brophy, Tess; Tyrer, J. H.

doi:10.1007/bf00548771

Cited by 48 publications

(18 citation statements)

References 5 publications

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“…Old age has been shown to alter the metabolism of several CYP3A substrate drugs, including a number of benzodiazepine derivatives (Greenblatt et al, 1989;von Moltke et al, 1995a;Cotreau et al, 2004). According to some studies, the clearance of the CYP3A substrate midazolam is reduced in healthy elderly subjects (Greenblatt et al, 1984;Smith et al, 1984). Studies have also shown age-related changes in the metabolism of alprazolam and TRZ (Greenblatt et al, 1983a(Greenblatt et al, ,b, 1991Bertz et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Effect of Age on in Vitro Triazolam Biotransformation in Male Human Liver Microsomes

Patki

Moltke²,

Harmatz³

et al. 2003

J Pharmacol Exp Ther

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We studied age-related changes in enzyme kinetic parameters in human liver microsomes (HLMs) in vitro, using triazolam (TRZ), an index of CYP3A activity. HLMs were prepared from male livers from four age groups, n ϭ 5 per group: A (14 -20 years), B (21-40 years), C (41-60 years), and D (61-72 years). Mean V max values in groups B and C for both 1-hydroxytriazolam (1-OH-TRZ) and 4-hydroxy-triazolam (4-OH-TRZ) formation were significantly greater as compared with groups A and D individually, as well as the net intrinsic clearance (sum of the two pathways). The mean net intrinsic clearance (Cl int ) values were 25.2, 89.8, 78, and 20.6 nl/min/mg protein in A, B, C, and D, respectively. TRZ Cl int correlated well with total CYP3A content (r s ϭ 0.84; P Ͻ 0.0001). Testosterone (TST) inhibited 1-OH-TRZ formation and activated 4-OH-TRZ formation in all age groups, with no significant differences among the groups; this suggests that the drug-drug interaction potential using TRZ and TST as index CYP3A substrates may not change with age. Reduced V max and Cl int for TRZ hydroxylation and CYP3A protein in livers from elderly men suggest reduced CYP3A gene expression in this group.There is considerable pharmacokinetic evidence suggesting that age-related changes occur in drug disposition (Schmucker, 1985;Greenblatt et al., 1989;von Moltke et al., 1995a). However, in some clinical studies, no age-related changes were demonstrated in the biotransformation of CYP3A substrates (see reviews by Greenblatt et al., 1982;Cotreau et al., 2004). Factors that could influence drug clearance in the elderly include the expression, content, and function of catalytically active enzymes, as well as liver mass, hepatic blood flow, and renal function (Vestal, 1982;Greenblatt et al., 1986). It has been shown that triazolam (TRZ) clearance is reduced in the elderly (Greenblatt et al., 1983a(Greenblatt et al., , 1991.In vitro studies could be helpful in examining the role of age on the metabolic activity of CYP3A and liver CYP3A content. However, the results of such studies have been inconsistent. Some studies using human liver microsomes (HLMs) have shown an age-related decline in CYP3A content (George et al., 1995;Sotaniemi et al., 1997) or total P450 activity (Sotaniemi et al., 1997), whereas others have found no change associated with age in content (Shimada et al., 1994;Transon et al., 1996) or activity of CYP3A (Schmucker et al., 1990;Hunt et al., 1992;Shimada et al., 1994;Transon et al., 1996).Previous in vitro studies have evaluated the effect of age on metabolite formation rate via CYP3A-mediated biotransformation, but without consideration for enzyme affinity (Hunt et al., 1992;Transon et al., 1996), HLMs were classified into one or more classes over a wide age range, and these studies did not evaluate the possible contribution of CYP3A5 to agerelated effects on CYP3A metabolism (Hunt et al., 1992;Shimada et al., 1994).To address these issues, we examined the effect of age on TRZ metabolism in HLMs from male donors ranging in ag...

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Section: Discussionmentioning

confidence: 99%

Effect of Age on in Vitro Triazolam Biotransformation in Male Human Liver Microsomes

Patki

Moltke²,

Harmatz³

et al. 2003

J Pharmacol Exp Ther

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“…In several European countries, a tablet form is available for oral use as a sedative-hypnotic. The disposition of midazolam has been studied extensively in healthy subjects after intravenous, intramuscular and oral administration (Allonen et al, 1981;Avram et al, 1983;Bornemann et al,1985Bornemann et al, , 1986Greenblatt et al, 1984;Heizmann & Ziegler, 1981;Heizmann et al, 1983;Holazo etal., 1988;Klotz & Zeigler, 1982;Smith et al, 1981Smith et al, , 1984. Midazolam is bound extensively to plasma proteins (94-96%), it has a large volume of distribution (0.8 to 1.91 kr-'), a high systemic clearance (0.24 to 0.731 h-kg-1) and a short elimination half-life (1.5 to 3 h).…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics of midazolam in patients with congestive heart failure.

Patel

Soni

et al. 1990

Brit J Clinical Pharma

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The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age-and weight-matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC-MS. In the CHF patients, the elimination half-life was prolonged (4 to 4.5 vs < 3 h), the systemic clearance was lowered (376 vs 551 ml min-1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml-'). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 1) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.

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“…It is well appreciated that aging increases the sensitivity to the sedative effects of midazolam and prolongs the duration of its action [1][2][3][4][5][6]. The increasing pharmacodynamic sensitivity due to aging has been explained by EEG data [1], the dose for disappearance of reaction to verbal commands [2], and psychometric tests [3].…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacodynamics and pharmacokinetics of benzodiazepine in the elderly have been reported to differ from those in younger individuals [1][2][3][4][5][6]. Accordingly, excessive sedation and delayed recovery from conscious sedation can occur in the elderly.…”

Section: Introductionmentioning

confidence: 99%