Pathway Doxorubicin Pathway, Pharmacokinetics

Pharmacokinetics
Diagrammatic representation of the transport and metabolism of doxorubicin.
Doxorubicin Pathway, Pharmacokinetics
dox slc22a16 gpx1 cat sod1 nqo1 xdh nos1 nos2 nos3 por xdh nqo1 ndufs cbr1 akr1a1 cbr3 akr1c3 abcb1 abcc1 abcc2 abcg2 ralbp1 dox
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Description

There are 3 main metabolic routes of anthracycline metabolism: one-electron reduction, two-electron reduction and deglycosidation. A large proportion of DOX however, approximately 50%, is eliminated from the body unchanged [Article:19442138].

Two-electron reduction of DOX to a secondary alcohol, DOXol is the major metabolic pathway [Article:19442138]. There are several enzymes that can carry out this reaction and their respective balance is different in different cell types [Article:18635746]. For example, AKR1A is considered the most important in heart tissue while CBR1 is the major contributor in liver [Articles:18635746, 12963485, 19442138]. CBR3 is also capable of forming DOXol [Article:20007405]. The role of AKR1C3 is unclear with some studies showing metabolism of DOX and others disputing it [Articles:18616992, 18635746, 12963485].

One-electron reduction of DOX is carried out by several oxidoreductases to form a DOX-semiquinone radical [Article:2555273]. These enzymes include mitochondrial NADH dehydrogenases present in the sarcoplasmic reticulum and mitochondria: NDUFS2, NDUFS3, and NDUFS7 (EC 1.6.99.3) [Articles:12688675, 2850270, 9618942] as well as cytosolic enzymes NADPH dehydrogenase (NQO1) [Article:12688675], xanthine oxidase (XDH) [Articles:12688675, 1911046] and nitric oxide synthases (NOS1, NOS2 and NOS3) [Articles:9333325, 15054088]. Re-oxidation of the DOX-semiquinone radical back to DOX leads to the formation of reactive oxygen species (ROS) and hydrogen peroxide [Article:9576481]. ROS, causing oxidative stress, can be deactivated by glutathione peroxidase (GPX1), catalase (CAT) and superoxide dismutase (SOD1) [Article:12751786]. It is the ROS released by this route of metabolism, rather than DOX-semiquinone. that some consider responsible for drug effects and adverse cardiotoxicity.

The third, minor route, deglycosidation, accounts for approximately 1-2% of DOX metabolism. This can be reductive to form the deoxyaglycone, or hydrolytic to form the hydroxyaglycone. The enzymes and their candidate genes for this process are less well characterized [Articles:19442138, 10813659]. In heart, no DOX hydroxyaglycone could be detected; it appears to be rapidly converted to DOXol aglycone [Article:10813659]. In heart, NADPH is required for formation of aglycones suggesting that NADPH dependent hydrolase and reductase-type glycosidases are responsible [Article:10813659]. NADPH-cytochrome P450 reductase (POR) was shown in vitro to metabolize DOX to DOX 7-deoxyaglycone [Articles:6305277, 10860924]. XDH and NQO1 were also implicated in this process [Article:10860924].

Transport
Several transporters have been shown be involved transporting doxorubicin including ABCB1, ABCC1, ABCC2, ABCG2, RALBP1 (export) and SLC22A16 (import) [Articles:12370750, 15164094, 7214365, 1352877, 3180056, 17704753, 11172691, 7954421, 12527936, 11410522, 17559346]. Genetic variation in transporters has been associated with drug resistance (see Doxorubicin Cancer PD Pathway for more details).

Pharmacogenomics (PGx)
That there exist considerable inter-individual variations in the pharmacokinetic parameters of DOX and DOXol has been known for a long time [Article:2265458]. However, the impact of genetic variants on DOX metabolism and response, including cardiotoxicity, has only recently begun to be studied. Historically, only cumulative anthracycline dose has been confirmed as a significant risk factor for DOX-induced cardiotoxicity [Article:6651020].

Authors: Caroline F. Thorn, Connie Oshiro, Sharon Marsh.
Citation:
Thorn Caroline F, Oshiro Connie, Marsh Sharon, Hernandez-Boussard Tina, McLeod Howard, Klein Teri E, Altman Russ B. "Doxorubicin pathways: pharmacodynamics and adverse effects" Pharmacogenetics and genomics (2010).
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History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (22)

Drugs/Drug Classes (1)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
DOX hydroxyaglycone doxorubicinol hydroxyaglycone 10813659, 19442138
DOX semiquinone doxorubicin, reactive oxygen species 19442138
doxorubicin DOX deoxyaglycone NQO1, POR, XDH 10860924, 19442138, 6305277
doxorubicin DOX hydroxyaglycone 19442138
doxorubicin DOX semiquinone NDUFS2, NDUFS3, NDUFS7, NOS1, NOS2, NOS3, NQO1, XDH 12688675, 15054088, 1911046, 2850270, 9333325
doxorubicin doxorubicinol AKR1A1, AKR1C3, CBR1, CBR3 12963485, 18616992, 18635746, 19442138, 20007405
reactive oxygen species reactive oxygen species CAT, GPX1, SOD1
doxorubicin doxorubicin ABCB1, ABCC1, ABCC2, ABCG2, RALBP1 11172691, 12370750, 12527936, 1352877, 15164094, 17704753, 3180056, 7214365, 7954421
doxorubicin doxorubicin SLC22A16 17559346
doxorubicin doxorubicin

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