The Effect of Age Upon the Affinity of Microsomal Mono-Oxygenase Enzymes for Substrate in Human Liver

Wynne, Hilary; Mutch, Elaine; James, O.F.W.; Wright, Peter V.; Rawlins, M. D.; Woodhouse, K. W.

doi:10.1093/ageing/17.6.401

Cited by 45 publications

(10 citation statements)

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“…These findings are consistent with other studies (George et al, 1995;Stevens et al, 2003). As in previous reports (Wynne et al, 1988), K m values did not differ significantly among the four age groups (Table 1). These findings indicate that the reduced intrinsic clearance in groups A and D is attributable to decreased V max values (Table 2), whereas the qualitative nature of the enzyme (indicated by K m values) does not differ significantly with age.…”

Section: Discussionsupporting

confidence: 93%

“…For drugs metabolized by first order kinetics, the affinity of the enzyme for substrate is an important determinant of reaction rate at low substrate concentrations. In a previous study (Wynne et al, 1988), no age-related changes were found in enzyme affinity. In our study, we evaluated effect of age on the metabolite formation rate and on the affinity, as well as on the estimated intrinsic clearance (V max /K m ).…”

Section: Discussionmentioning

confidence: 65%

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

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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: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 65%

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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“…Age-associated changes in body composition may also affect the V d or Q of a drug. [41] Although CYP activity in human liver microsomes, cultured hepatocytes and liver slices is not affected by the age of the donor, [39,42] CYP2C19 activity shows a decrease with age and has higher interindividual variability in older subjects. [15] In the present analysis, differences in the clearance of roflumilast were not associated with age, whereas clearance of roflumilast N-oxide was estimated to decrease by 25.6% between the ages of 40 and 75 years.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model

Lahu

Hünnemeyer²,

Diletti³

et al. 2010

Clinical Pharmacokinetics

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“…We have investigated total microsomal protein content, which is a general indicator of the content of membrane-bound enzymes, in livers from humans over a wide age range and have noted no decrease (Woodhouse et al 1984;Wynne et al 1988). We have investigated total microsomal protein content, which is a general indicator of the content of membrane-bound enzymes, in livers from humans over a wide age range and have noted no decrease (Woodhouse et al 1984;Wynne et al 1988).…”

Section: Human Studiesmentioning

confidence: 99%

Age-Related Changes in Hepatic Function

Woodhouse

Wynne

1992

Drugs & Aging

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An age-related decrease in the hepatic clearance of many drugs has been reported. Several mechanisms have been proposed, but only some are supported by hard evidence. Liver volume declines with age, as does hepatic blood flow--changes which may largely account for the reduced clearance of capacity- and flow-limited drugs, respectively. Age-related histological changes in the liver are minor and of uncertain significance; standard liver function tests do not change significantly with aging. There is, as yet, no direct evidence of a generalised fall in hepatic drug-metabolising enzyme activities in aging humans measured in vitro, but some in vivo studies suggest that certain very specific cytochrome P450 isoenzymes may be affected by aging, especially in men. Finally, there may be an age-related decline in the response to environmental influences.

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The Effect of Age Upon the Affinity of Microsomal Mono-Oxygenase Enzymes for Substrate in Human Liver

Cited by 45 publications

References 0 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

Population Pharmacokinetic Modelling of Roflumilast and Roflumilast N-Oxide by Total Phosphodiesterase-4 Inhibitory Activity and Development of a Population Pharmacodynamic-Adverse Event Model

Age-Related Changes in Hepatic Function

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