Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.

Dj, Greenblatt; Divoll, Marcia; Abernethy,; Moschitto, LJ; Smith, Roger; Shader, R I

doi:10.1111/j.1365-2125.1983.tb01503.x

Cited by 91 publications

(33 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). However, in some human in vivo studies, no age-related changes were demonstrated in the biotransformation of CYP3A substrates (see reviews by Greenblatt et al, 1982; Cotreau et al, .…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Patki

Moltke²,

Harmatz³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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

View full text Add to dashboard Cite

show abstract

“…The findings suggest that INH impairs the hepatic capacity for microsomal oxidation of triazolam, which is biotransformed to at least two hydroxylated metabolites that are rapidly conjugated and excreted (Eberts et al, 1981). (Greenblatt et al, 1983) or cimetidine coadministration (Abernethy et al, 1983a) (Wilkinson & Shand, 1975 (Abemethy et al, 1983b;Greenblatt, 1981;Greenblatt et al, 1982). The findings emphasize the differential control of drug oxidation and conjugation.…”

Section: Discussionmentioning

confidence: 99%

“…The influence of INH on drug conjugating capacity is not established. The present study evaluated the influence of INH on the kinetics of triazolam (Halcion), a triazolobenzodiazepine derivative with a short elimination half-life recently released as a hypnotic agent in the United States (Eberts et al, 1981;Greenblatt et al, 1983;Pakes et al, 1981). Also evaluated was the effect of INH on the kinetics of oxazepam (Serax), a benzodiazepine anxiolytic metabolized principally by conjugation to glucuronic acid (Greenblatt, 1981 (Ochs et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation.

Ochs¹,

Dj²,

Knüchel³

1983

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Healthy volunteers received a single dose of triazolam (0.5 mg) or oxazepam (30 mg) on two occasions, once in the control state and again during coadministration of isoniazid (INH) base, 180 mg day. INH coadministration prolonged triazolam half-life (3.3 vs 2.5 h, P < 0.05) and increased total area under the curve (38.6 vs 26.5 ng ml-' h, P < 0.01) consistent with a reduction of apparent oral clearance (3.9 vs 6.8 ml minm 'kg-', 0.05 < P < 0.1). INH coadministration had no influence on the kinetics of oxazepam. INH impairs hepatic microsomal oxidation of triazolam, leading to reduced first-pass hepatic extraction as well as prolonged half-life. However INH had no influence on oxazepam conjugation.

show abstract

“…Its major metabolic pathway involves hepatic microsomal oxidation, leading to one or more hydroxylated metabolites that are rapidly conjugated and excreted (Eberts et al, 1981). Triazolam has a relatively high hepatic clearance, and a short half-life usually ranging from 2 to 5 h in healthy individuals (Ochs et al, 1983;Greenblatt et al, 1983;Smith et al, 1983a;Stoehr et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

Ochs

Burstein

1987

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15‐30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml‐1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half‐life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min‐1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.

show abstract

Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity.

Cited by 91 publications

References 29 publications

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

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

Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation.

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

Contact Info

Product

Resources

About