Pharmacokinetics and Metabolism of TCAs

Most of TCAs are well absorbed and reach peak plasma concentrations within 2-12 h. Owing to their lipophilic properties, they have a very large volume of distribution. Many of TCAs are tertiary amines and are metabolized by the cytochrome P450 isoenzyme system to secondary amines, which are also active. Some TCAs are metabolized to hydroxylated metabolites that may also be active and are further metabolized by glucuronidation. Some pharmacokinetics properties of TCAs are summarized in Table 1. When interpreting data, it is important to keep in mind that these values, at best, are approximate, and there is a considerable inter-individual variability. Some of the factors responsible for these variations are discussed below in section 2.2.

Table 1

Pharmacokinetic Properties of tricyclic antidepressants (TCAs)

Table 1

Pharmacokinetic Properties of tricyclic antidepressants (TCAs)

Active

Average

Vd

Oral

Average

Therapeutic

Drug

metabolite

Half-Life

(L/kg)

Bioavail-

Protein

Range

(hours)

ability

Binding

(ng/mL)

Amitriptyline

Nortriptyline

21

15

50

95

120-250a

Desipramine

NA

20

42

40

80

75-300

Doxepin

Nordoxepin

17

20

27

90

150-250a

Imipramine

Desipramine

12

18

40

90

150-250a

Nortriptyline

NA

30

18

50

92

50-150

Protriptyline

NA

80

13

75

95

70-250

Trimipramine

NA

27

32

50

90

100-250

Vd = Volume of distribution.

NA, no significantly active metabolite. a It is total concentration of the antidepressant and its active metabolite. TCA concentrations >500 ng/mL should be considered potentially toxic.

Vd = Volume of distribution.

NA, no significantly active metabolite. a It is total concentration of the antidepressant and its active metabolite. TCA concentrations >500 ng/mL should be considered potentially toxic.

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