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MINI REVIEW
Drug metabolism and drug transport of the 100 most
prescribed oral drugs
Ditte B. Iversen | Nanna Elman Andersen |
Ann-Cathrine Dalgård Dunvald | Anton Pottegård | Tore B. Stage
Clinical Pharmacology, Pharmacy and
Environmental Medicine, Department of
Public Health, University of Southern
Denmark, Odense, Denmark
Correspondence
Tore B. Stage, Clinical Pharmacology,
Pharmacy and Environmental Medicine,
Department of Public Health, University
of Southern Denmark, J.B. Winsløws Vej
19, 2
nd
floor, 5000 Odense C, Denmark.
Email: tstage@health.sdu.dk
Funding information
This work was funded by Novo Nordisk
Foundation (NNF19OC0058275),
Lundbeck Foundation Fellowship
(R307-2018-2980) and Danish Cancer
Society (R279-A16411).
Abstract
Safe and effective use of drugs requires an understanding of metabolism and
transport. We identified the 100 most prescribed drugs in six countries and
conducted a literature search on in vitro data to assess contribution of Phase I
and II enzymes and drug transporters to metabolism and transport.
Eighty-nine of the 100 drugs undergo drug metabolism or are known sub-
strates for drug transporters. Phase I enzymes are involved in metabolism of
67 drugs, while Phase II enzymes mediate metabolism of 18 drugs. CYP3A4/5
is the most important Phase I enzyme involved in metabolism of 43 drugs fol-
lowed by CYP2D6 (23 drugs), CYP2C9 (23 drugs), CYP2C19 (22 drugs),
CYP1A2 (14 drugs) and CYP2C8 (11 drugs). More than half of the drugs
(54 drugs) are known substrates for drug transporters. P-glycoprotein (P-gp) is
known to be involved in transport of 30 drugs, while breast cancer resistance
protein (BCRP) facilitates transport of 11 drugs. A considerable proportion of
drugs are subject to a combination of Phase I metabolism, Phase II metabolism
and/or drug transport.
We conclude that the majority of the most frequently prescribed drugs depend
on drug metabolism or drug transport. Thus, understanding variability of drug
metabolism and transport remains a priority.
KEYWORDS
ADME, CYP3A4, drug metabolism, drug transport, P-gp
1|INTRODUCTION
The use of medicines is increasing worldwide.
1
A
Danish study found that 51% of individuals ≥75 years
are prescribed five or more different medications.
2
Enzymatic drug metabolism and drug transport are
important for absorption, disposition, metabolism and
elimination of a drug within the body.
3
Drug
metabolism and drug transport are known to vary both
between and within individuals, and this is a problem
as it causes variable treatment efficacy and toxicity.
Variation in drug metabolism and drug transport may
be caused by drug–drug interactions,
3
epigenetics,
4
genetic polymorphisms in genes that encode drug-
metabolizing enzymes or drug transporters
[e.g. cytochrome P450 (CYP)2D6,CYP2C9 and
Received: 18 May 2022 Revised: 11 August 2022 Accepted: 11 August 2022
DOI: 10.1111/bcpt.13780
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former
Nordic Pharmacological Society).
Basic Clin Pharmacol Toxicol. 2022;1–14. wileyonlinelibrary.com/journal/bcpt 1
CYP2C19],
5
or intrinsic (e.g. sex and inflammation)
and extrinsic factors (e.g. diet and chemical exposure
from the environment).
6
A previous literature study described the Phase I
enzymes involved in drug metabolism of the
200 most prescribed drugs in the United States.
7
In
this paper, we provide an updated mapping of Phase I
metabolism but also include Phase II metabolism and
drug transporters relevant for the 100 most prescribed
drugs in five European countries and Australia. We
included data from six countries to make the list more
international. Furthermore, we summarized the total
enzyme and transporter contribution to understand the
number of drugs that will be affected because of varia-
tion in metabolism or drug transport. Finally, we
reviewed main aspects from the literature of the most
important Phase I and II enzymes and drug
transporters.
2|METHODS
We identified the 100 most prescribed drugs in five
European countries and Australia and performed a litera-
ture search for each drug to understand its metabolism
and transport.
2.1 |Identifying the Top 100 most
prescribed drugs
We obtained data on prescription drug use from six
countries: Denmark, Sweden, Norway, England,
Scotland and Australia. Data were available upon spe-
cific requests to collaborators in the six countries. For
each country, we identified the most prescribed drugs.
The ranking of drugs, on the individual lists, was
based on different measures. Data from Denmark and
Sweden were based on the number of prescriptions per
1000 citizens, data from Norway were based on the
number of unique individuals buying a drug, data from
England and Scotland were based on the number of
dispensed items, and data from Australia were based
on the number of prescriptions. Medications that con-
tain two active substances were split into their individ-
ual components; for example, the drug combination of
codeine and paracetamol was counted as the use of
both drugs individually. We only included orally
administered drugs for systemic treatment, thus exclud-
ing inhalation preparations, intravenous preparations,
dermatological preparations, drugs with no absorption
from the intestine and dietary supplements. Only pre-
scription data from pharmacies were available, thus
excluding prescription data from hospitals. As the
Norwegian data contained the lowest number of indi-
vidual medications (n=179), we restricted all the
remaining datasets to the 179 most used medications
as well. For each country, we calculated the percentage
the individual 179 drugs on the list constituted. Based
on these percentages, we calculated the average rank-
ing across all six countries with the following equation,
where X was the percentage of a specific drug in the
six countries:
Share spent on avarage ¼XDK þXSE þXNO þXSC þXUK þXAUS
ðÞ
6:
A drug was assigned X =0 if it was absent from the
individual list of a country. Calculation of the Top
100 drug list was carried out using the Stata Statistical
Software: Release 16 (StataCorp College Station, TX:
StataCorp LLC, USA).
From the final list, we chose the 100 most prescribed
drugs and conducted a literature search.
2.2 |Search strategy
Two authors (DBI and NA) performed a literature search
from January to October 2021 using the database
PubMed (Medline). We performed separate literature
searches for drug-metabolizing enzymes and drug
transporters.
The following search strings were applied for the indi-
vidual drugs:
Drug metabolism: (drug name AND (hepatic OR Liver
OR intestinal OR CYP OR cytochrome P450) AND
(pharmacokinetic OR ADME OR metabolism OR metab-
olized) AND in vitro).
Drug transporter: (drug name AND substrate AND
(transporter OR transport) AND (elimination OR excre-
tion OR excreted OR efflux OR uptake)).
The search term ‘drug name’was defined as the drug
name specified on the Top 100 list. Synonyms for the
drug name were automatically included by PubMed, for
example, a search for paracetamol also included acet-
aminophen. Additionally, we identified and included rel-
evant references from articles identified via the search
string. We included articles regardless of publication year
but strived to use the most recently published.
Furthermore, we conducted a literature search for
each drug to determine if the drug was categorized as a
prodrug. A prodrug was defined as an inactive substance
that needs to be converted to a pharmacologically active
substance through metabolism or physico-chemical
processes.
8
2IVERSEN ET AL.
2.3 |Study selection for Top 100 most
prescribed drugs
We created three inclusion criteria before conducting the
literature search. The inclusion criteria were that articles
included in the analysis had to be specific for the drug in
question and had to report (i) original data, (ii) human
in vitro studies and (iii) data of Phase I or II metabolism
or drug transport.
Documents from Food and Drug Administration
(FDA) or European Medicines Agency (EMA)
[e.g. Summary of Product Characteristics (SmPCs) or
Highlights of Prescribing Information] were included in
the analysis if they were found as references to articles in
the literature search. Two authors (DBI and NA) were
each responsible for the search of 50 drugs from the Top
100 list and independently screened relevant articles
found in the literature search. We did not screen all arti-
cles obtained in the literature search, but only until the
metabolism and transport of a drug was confirmed
through an acceptable article that was deemed valid by
meeting the inclusion criteria. After completion of the lit-
erature search, one author (TBS) double-checked the
results to uncover any mistakes or errors concerning the
matching of drugs with enzymes and drug transporters
known to be involved in drug metabolism or drug
transport.
2.4 |Data analysis
For the drug in question, we flagged an enzyme or trans-
porter as major if one of two conditions were achieved,
(i) if the article from the literature search stated that the
enzyme or transporter were responsible for more than
50% of the fraction metabolized or transported or (ii) if
an original paper defined an enzyme or transporter as
‘major’. We did not define a lower cut-off to categorize
enzymes or transporters as minor based on contribution
to drug metabolism or drug transport. Furthermore, the
status of the drug (prodrug or not) was recorded. We
divided Phase I enzymes into subcategories of isoforms,
for example, CYP2C9 and CYP2D6, and calculated the
number of the 100 drugs metabolized by each isoform.
All isoforms from the Top 100 list were included equally
in the calculation regardless of if they were flagged as
major enzyme or transporter. Isoforms metabolizing ≤5
of the 100 drugs were categorized as ‘Others’. CYP3A4
and CYP3A5 isoforms were grouped as one isoform,
CYP3A4/5, as they share 80% structural similarity and
have overlapping substrate specificity making it difficult
to distinguish the isoforms.
9
For Phase II enzymes, we only divided the uridine
50-diphospho-glucuronosyltransferases (UGTs) into
isoforms, for example, UGT2B7 and UGT1A9, as UGTs
are the largest Phase II superfamily.
10
The remaining
Phase II enzymes were grouped to the superfamily sulfo-
transferases (SULT). For drug transporters, we described
P-glycoprotein (P-gp), breast cancer resistance protein
(BCRP) and organic anion transporting polypeptide
(OATP) in isoforms and grouped organic anion
transporter (OAT), organic cation transporter (OCT),
multidrug resistance-associated protein 1–4 (MRP1–4)
and multidrug and toxic compound extrusion (MATE)
into superfamilies. Isoforms and superfamilies, of both
Phase II enzymes and drug transporters, were grouped as
‘Others’if they metabolized or transported ≤2 of the
100 drugs.
For both Phase I and Phase II enzymes and drug
transporters, we calculated the substrate overlap within
each group (Phase I, Phase II and drug transporters). We
grouped substrate overlap in the following groups for
Phase I enzymes: 1–5 drugs, 6–10 drugs and more than
10 drugs. For Phase II enzymes and drug transporters, we
changed the range of substrate overlap to better reflect
substrate overlap within these groups. We grouped sub-
strate overlap as 1–2 drugs, 3–4 drugs and more than 4
drugs. We also calculated the substrate overlap between
the drug transporters (P-gp, BCRP and OATP1B1/3) and
four CYP enzymes (CYP3A4/5, CYP2D6, CYP2C9 and
CYP2C19). We grouped substrate overlap between drug
transporters and CYP enzymes as 1–5 drugs, 6–10 drugs
and more than 10 drugs. Data visualization was carried
out using the statistical software RStudio Team (2021)
(RStudio: Integrated Development Environment for
R. RStudio, PBC, Boston, MA; http://www.rstudio.com/).
3|RESULTS
Of the 100 most prescribed drugs (Table S1), 89 drugs are
known to be subject to drug metabolism or drug trans-
port, while the remaining 11 drugs are not metabolized
or known to be substrates for drug transporters. Phase I
enzymes metabolize 67 drugs, 18 drugs are metabolized
by Phase II enzymes, and 54 drugs are known to be trans-
ported by drug transporters (Figure 1). A total of 27 drugs
are known to be substrates for both Phase I metabolism
and drug transport, while only seven drugs are known to
be substrates for Phase I and Phase II metabolism and
drug transport (Figure 1). We included a supplementary
table (Table S2) with a ranked list of the 179 drugs from
each country combined with the percentage each drug
constituted from the list.
IVERSEN ET AL.3
3.1 |Phase I metabolism
CYP3A4/5 is the most important Phase I enzyme as it is
involved in the metabolism of 43 of the 100 drugs, fol-
lowed by CYP2D6 (23 drugs), CYP2C9 (23 drugs),
CYP2C19 (22 drugs), CYP1A2 (14 drugs) and CYP2C8
(11 drugs) (Figure 2).
3.1.1 | CYP3A4/5
We find that CYP3A4/5 metabolizes 43 of the 100 drugs
and has substrate overlap with three CYP isoforms,
CYP2D6, CYP2C9, and CYP2C19 (>10 drugs for all
enzymes; Figure 2).
CYP3A4/5 is predominantly expressed in the liver
and intestine and is the most dominant drug-
metabolizing enzyme in the body.
11,12
Top 3 drugs from
our list with CYP3A4/5 as the major enzyme include
bisoprolol, ethinylestradiol and zopiclone.
CYP3A4/5 is transcriptionally regulated by pregnane
X receptor (PXR) and constitutive androstane receptor
(CAR). PXR and CAR are members of the nuclear recep-
tor (NR) superfamily, and PXR is one of the most impor-
tant receptors in the regulation of metabolism and drug
transport. Flucloxacillin (number 61 of the 100 drugs),
dicloxacillin (number 77) and rifampicin (not on the list)
are examples of PXR agonists that cause upregulation of
CYP3A4 by PXR.
13,14
Contrary, ciprofloxacin (number
92) is an example of a moderate CYP3A4 inhibitor.
15
The
time it takes for induction or inhibition to occur and the
time it takes for an enzyme to recover from this is impor-
tant when optimizing pharmacotherapy. One clinical
trial investigated the recovery time for CYP3A4 after use
of rifampicin for 7 days and discovered that 8 days was
needed to recover from rifampicin-mediated induction.
16
Another clinical trial investigated CYP3A4 induction
after 28 days of rifampicin treatment. Discontinuation for
28 days was needed to completely recover from
rifampicin-mediated induction.
17
Duration of competitive
inhibition depends on the elimination half-life of the
inhibitor, whereas duration of non-competitive inhibition
and induction depends on different biological factors
such as de-induction of PXR-driven transcription (e.g. for
CYP3A4), degradation of induced mRNAs and their
encoded proteins in the liver and gut, CYP protein syn-
thesis and cell turnover.
17
Food, drinks, herbal drugs and inflammation can also
regulate the expression of CYP3A4/5 and lead to drug
concentrations out of the therapeutic range. Both Seville
FIGURE 2 Number of drugs metabolized by Phase I enzymes
is illustrated with increasing circle size. The size and darkness of
the lines between enzymes illustrate the substrate overlap between
enzymes. Thin/light-grey line corresponds to 1–5 drugs as substrate
overlap. Medium/grey line corresponds to 6–10 drugs as substrate
overlap. Thick/black line corresponds to >10 drugs as substrate
overlap. Overlap within a group is not illustrated in the figure, but
we refer to Table S1 for further information. The group Other
includes CYP1A1, CYP2E1, CP2C18, CYP2J2, CYP3A3, CYP3A7,
CYP2A6, CYP1B1, AO, FMO and MAO-A +B. AO, aldehyde
oxidase; CES, carboxylesterase; CYP, cytochrome P450 enzyme;
FMO, flavin-containing monooxygenase; MAO, monoamine
oxidase.
FIGURE 1 Number of the 100 most prescribed drugs
metabolized by Phase I enzymes or Phase II enzymes or
transported by drug transporters. Overlapping areas reflect a
combination of pathways. Of the 100 most prescribed drugs,
11 drugs are not metabolized or transported.
4IVERSEN ET AL.
orange and grapefruit inhibit CYP3A4.
18
St. John’s wort,
a herbal drug used against depression, is a potent ligand
to PXR and an inducer of CYP3A4.
19
CYP3A4/5 can also
be downregulated by proinflammatory cytokines during
inflammation.
20
Despite multiple studies on genetic polymorphism in
CYP3A4, there is currently no evidence of common and
clinically relevant polymorphisms in CYP3A4. Individuals
with CYP3A5 genetic polymorphism can be characterized
as CYP3A5 expressors or as CYP3A5 non-expressors.
CYP3A5 non-expressors make up 80%–85% of Caucasians,
leading CYP3A5 expressors to be the minority in
Europe.
21
This is in contrast to the Asian and African
American population where 60%–73% and 32% are
CYP3A5 non-expressors, respectively.
22
The Clinical Phar-
macogenetics Implementation Consortium (CPIC) guide-
line for treatment with tacrolimus (CYP3A4/5 substrate)
(not on the list) recommends a standard starting dose for
CYP3A5 non-expressor and a higher starting dose for
CYP3A5 expressors.
21
3.1.2 | CYP2D6
Our findings show that CYP2D6 metabolizes 23 of the
100 drugs and has the largest substrate overlap with
CYP3A4/5 (10 drugs; Figure 2). CYP2D6 is mainly
expressed in the liver.
11,12
It is the second most impor-
tant CYP enzyme in our review, and it accounts for
5% of the total CYP protein content in the human
liver.
23
Top 3 drugs from our list with CYP2D6 as the
major enzyme include metoprolol, venlafaxine and
fluoxetine.
CYP2D6 is not susceptible to enzyme induction by
drugs,
24
but CYP2D6 expression is increased during preg-
nancy.
25
In a clinical trial, the plasma metabolic ratio of
the CYP2D6 probe dextromethorphan (not on the list)
decreased by 53% during pregnancy compared to after
pregnancy.
25,26
The antidepressants sertraline (number
19) and fluoxetine (number 52) are inhibitors of
CYP2D6.
27
Inhibition lasts 5 days for sertraline and
42 days for fluoxetine after discontinuation.
27
Clinicians
should be cautious when prescribing CYP2D6 substrates
following initiation and discontinuation of these
antidepressants.
27
Polymorphism in CYP enzymes plays a critical role,
especially in CYP2D6. A meta-analysis showed that the
efficacy of metoprolol (number 16) is higher in poor
metabolizers compared to non-poor metabolizers.
28
CPIC
guideline recommends alternative analgesics to the two
prodrugs, codeine (number 7) and tramadol (number 21),
in poor metabolizers or ultrarapid metabolizers,
29
as they
are more likely to experience poor pain relief or more
adverse effects compared to intermediate metabolizers
and extensive metabolizers.
30
The nuclear factor 1B
(NFIB) was recently discovered to regulate CYP2D6 gene
expression in vitro.
31
The same study showed that NFIB
rs28379954 T>C carriers that were also CYP2D6 exten-
sive metabolizers had comparable CYP2D6 activity to
ultrarapid metabolizers. This highlights that NFIB poly-
morphisms are important to consider in CYP2D6 drug
metabolism.
31
3.1.3 | CYP2C9
We show that CYP2C9 metabolizes 23 of the 100 drugs
and has substrate overlap with CYP3A4/5 and
CYP2C19 (>10 drugs for each enzyme; Figure 2).
CYP2C9 is predominantly expressed in the liver and
gastrointestinal tract.
11,12
The CYP2C family contains
CYP2C8, CYP2C9 and CYP2C19, which in total com-
prise 33% of the total CYP protein content in the liver,
with CYP2C9 accounting for 24%.
23
Top 3 drugs from
our list with CYP2C9 as the major enzyme include
naproxen, diclofenac and warfarin. CYP2C9 is regu-
lated by three nuclear receptors: PXR, CAR and gluco-
corticoid receptor (GR).
32
S-warfarin (number 45) is a CYP2C9 substrate with
a narrow therapeutic index.
33
Fluconazole (number 87)
inhibits CYP2C9, and an epidemiological study found
that coadministration of fluconazole with warfarin
leads to an increase in mean international normalized
ratio (INR) of 0.83.
34
This clinically relevant increase
in INR can result in adverse effects.
34
Dicloxacillin
(number 77) is an inducer of CYP2C9 through PXR
activation.
13
Two epidemiological studies showed that
coadministration of dicloxacillin and warfarin leads to
a decrease in mean INR at 0.62 after 2–4 weeks of
dicloxacillin exposure
35
and an increased risk of ischae-
mic stroke and systemic embolism (hazard ratio
2.19).
36
Genetic polymorphisms may affect CYP2C9 activity.
CYP2C9*2 and CYP2C9*3 are the most studied genotypes
and carriers of either have decreased CYP2C9 activity.
The plasma clearance of S-warfarin is decreased by 56%
(CYP2C9*1/3), 70% (CYP2C9*2/3) and 75% (CYP2C9*3/3)
compared to wild type (CYP2C9*1/1).
37
Three large ran-
domized clinical trials investigated if genotyping before
initiating anticoagulant therapy improves the percentage
of time in the therapeutic INR range. The studies reached
contradicting conclusions, which complicated implemen-
tation of CYP2C9-guided treatment with warfarin.
38–40
The CPIC guideline for warfarin therapy only recom-
mends dosing based on genotype if it is known before ini-
tiating treatment.
41
IVERSEN ET AL.5
3.1.4 | CYP2C19
CYP2C19 metabolizes 22 of the 100 drugs and has consid-
erable substrate overlap with CYP2C9 and CYP3A4/5
(>10 drugs for each enzyme Figure 2). CYP2C19 is
expressed in the liver and gastrointestinal tract.
11,12
Top
3 drugs from our list with CYP2C19 as the major enzyme
include omeprazole, pantoprazole and esomeprazole.
CYP2C19 is regulated by the same three nuclear recep-
tors as CYP2C9 (PXR, CAR and GR).
42
Rifampicin (not
on the list) is an inducer of this enzyme through both
CAR and PXR, and dexamethasone (number 60) induces
CYP2C19 through GR.
42
CYP2C19 polymorphisms have been widely investi-
gated, and some variants might be clinically relevant.
Carriers of CYP2C19*17 are characterized as ultrarapid
metabolizers, while carriers of CYP2C19*2/3 are char-
acterized as poor metabolizers.
43
Patients that carry
CYP2C19*2 who are treated with citalopram (number
30), a substrate of CYP2C19, had lower odds of toler-
ance to the drug.
44
A clinical study showed that indi-
viduals carrying CYP2C19*2 and CYP2C19*3 had lower
omeprazole (number 4) metabolism compared to indi-
viduals carrying CYP2C9*1.
45
The same study showed
that administration of the CYP2C19 inhibitor fluvoxa-
mine (not on the list) reduced omeprazole metabolism
in individuals carrying CYP2C19*1, but it had no
impact on the metabolism of omeprazole in CYP2C19*2
and CYP2C19*3 carriers.
45
CYP2C19 intermediate and
poor metabolizers who receive the prodrug clopidogrel
(number 36) experience reduced platelet inhibition and
increased risk of major adverse cardiovascular and
cerebrovascular events.
46
CPIC guideline recommends
considering an alternative to clopidogrel in intermedi-
ate metabolizers and to avoid clopidogrel in poor
metabolizers.
46
3.1.5 | CYP1A2
Our review shows that CYP1A2 metabolizes 14 of the
100 drugs and has substrate overlap with CYP3A4/5,
CYP2C9, CYP2C19 and CYP2D6 (6–10 drugs for each
enzyme; Figure 2). CYP1A2 is predominantly expressed
in the liver.
11,12
From our list, CYP1A2 is not categorized
as the major enzyme in drug metabolism, but the Top
3 CYP1A2 substrates from our list are naproxen, ethiny-
lestradiol and mirtazapine. CYP1A2 is transcriptionally
regulated by aryl hydrocarbon receptor (AhR), which is a
ligand-activated transcription factor.
47
Several drugs induce CYP1A2.
48
Omeprazole (number
4) is an inducer of CYP1A2 in vitro.
49
The most potent
CYP1A2 inhibitors are planar molecules with a small
volume that easily fit into the active site of CYP1A2. They
often contain methyl, chloro or fluoro substitutions, for
example, ciprofloxacin (number 92).
50
Ciprofloxacin and
oral contraceptives containing ethinylestradiol (number
27) and gestodene were investigated for inhibition of tiza-
nidine metabolism (CYP1A2 substrate) (not on the
list).
51–53
Ciprofloxacin is a stronger inhibitor than oral
contraceptives; however, care should be taken when tiza-
nidine is administered to oral contraceptive users, as tiza-
nidine has a narrow therapeutic range.
51
The activity of CYP1A2 is subject to individual differ-
ences from genetic factors
54
and environmental factors
such as smoking.
48
Clozapine (not on the list) is a sub-
strate of CYP1A2 and is an antipsychotic drug where
therapeutic drug monitoring is used.
55
A meta-analysis
recommended decreasing the dosage of clozapine by 30%
for patients who smoke and suddenly stop smoking and
to analyse clozapine blood levels.
55
3.1.6 | CYP2C8
We find that CYP2C8 metabolizes 11 of the 100 drugs
and has substrate overlap with CYP3A4/5, CYP2C9 and
CYP2C19 (6–10 drugs for each enzyme; Figure 2).
CYP2C8 is highly expressed in the liver.
11,12
From our
list, CYP2C8 is not categorized as the major enzyme in
the metabolism of the 100 most used drugs, but the Top
3 CYP2C8 substrates from our list are ibuprofen, ethiny-
lestradiol and zopiclone. The transcriptional regulation of
CYP2C8 is the same as for CYP2C9 and CYP2C19 (PXR,
CAR and GR).
56
Felodipine (number 76) is an example of a potent
inhibitor in vitro,
57
and trimethoprim (number 55) is a
weak inhibitor of CYP2C8 both in vitro and in vivo.
58
Clo-
pidogrel (number 36) is a CYP2C8 inhibitor via its metab-
olite, clopidogrel acyl-β-D-glucuronide.
59
A retrospective
study showed that patients treated with paclitaxel
(CYP2C8 substrate) (not on the list) had a 2-fold
increased risk of developing neuropathy Grade 2 or higher
when co-treated with clopidogrel.
60
Only a few CYP2C8
inducers have been discovered. Dexamethasone (number
60), a corticosteroid, induces CYP2C8 through binding to
GR. Rifampicin (not on the list) induces CYP2C8 and
increases the expression of the enzyme through PXR
activation.
56
The genetic polymorphism CYP2C8*3 is the most
investigated polymorphism in CYP2C8. The allele is com-
mon in Caucasians but rare in African and Asian popula-
tions.
61
Many studies have investigated this allele, but
data are conflicting regarding the effect on metabolism,
and the activity of CYP2C8*3 might be substrate
dependent.
62,63
6IVERSEN ET AL.
3.2 |Phase II metabolism
The UGT superfamily is the most important Phase II
superfamily and is involved in the metabolism of 17 of
the most used drugs, followed by sulfotransferase
(SULT) that metabolizes three of the 100 drugs
(Table S1).
3.2.1 | UGTs
UGT superfamily can be divided into four families,
UGT1, UGT2, UGT3 and UGT8; however, UGT3 and
UGT8 are not significant in drug metabolism.
64
We high-
light UGT1A and UGT2B as the most important family
members for drug metabolism. We show that UGT2B7 is
responsible for metabolism of nine of the 100 drugs
(Figure 3). UGT1A3 and UGT1A9 are the second most
important Phase II enzymes, and they metabolize eight
of the 100 drugs (Figure 3). UGT2B7 and UGT1A9 share
the largest substrate overlap with five drugs. UGTs are
mainly expressed in the liver and intestine.
64
UGTs are marked as the major enzyme for two of
the top 100 drugs; this includes diclofenac and
telmisartan. Different nuclear receptors are involved in
regulation of different isoforms in the UGT superfam-
ily. This includes AhR, CAR, PXR, farnesoid X receptor
(FXR), liver X receptor (LXR) and peroxisome
proliferator-activated receptor (PPAR).
65
Studies investi-
gating the regulation of UGTs are sparse compared to
CYP enzymes. However, some drugs have been identi-
fied as inhibitors of UGTs in vitro though few are con-
firmed in in vivo studies. UGT1A1 is involved in
glucuronidation of bilirubin, and a study found that
tyrosine kinase inhibitors inhibit UGT1A1, which
increases the risk of hyperbilirubinaemia in patients.
66
Atazanavir (not on the list) is used to treat HIV and
inhibits UGT1A1. If UGT1A1 genotype is known before
treatment start, CPIC guideline recommends consider-
ing an alternative agent to atazanavir in poor metaboli-
zers as there is an increased risk of jaundice.
67
In vitro
studies have also shown that UGTs are subject to
induction. Many UGT inducers also induce other
enzymes such as CYP enzymes and include rifampicin
(not on the list), phenobarbital (not on the list) and
carbamazepine (not on the list).
68
In vivo studies inves-
tigating induction or inhibition are difficult to conduct
since there are few good and specific probe drugs for
UGT isoforms.
69
3.3 |Drug transporters
P-gp is the most important drug transporter and known
to transport 30 of the 100 drugs. Breast cancer resistance
protein (BCRP) is known to transport 11 drugs, and
organic anion transporting polypeptide 1B1 (OATP1B1)
and OATP1B3 are both known to transport nine drugs
(Figure 4).
3.3.1 | P-gp
We find that P-gp is known to transports 30 drugs and
has the largest substrate overlap with BCRP (five drugs;
Figure 4). Substrate overlap of 3-4 drugs is shared with
OATP1B1 and OATP1B3, organic cation transporter
(OCT), organic anion transporter (OAT) and multi-drug
resistance protein 1–4 (MRP1–4) (Figure 4). The overall
largest substrate overlap for P-gp is with CYP3A4/5 (>10
drugs; Figure 5A), and a minor substrate overlap is seen
with CYP2D6, CYP2C9 and CYP2C19 (6–10 drugs;
Figure 5A).
P-gp has wide tissues distribution, for example, brain,
endocrine tissues, gastrointestinal tract, liver and kid-
ney.
11,12
It belongs to the ATP binding cassette (ABC)
transporter superfamily, and the function of P-gp is to
FIGURE 3 Number of drugs metabolized by Phase II enzymes
is illustrated with increasing circle size. The size and darkness of
the lines between enzymes illustrate the substrate overlap. Thin/
light-grey line corresponds to 1–2 drugs as substrate overlap.
Medium/grey line corresponds to 3–4 drugs as substrate overlap.
Thick/black line corresponds to >4 drugs as substrate overlap.
Overlap within a group is not illustrated in the figure, but we refer
to Table S1 for further information. The group Other contains
UGT1A4, UGT1A6 and UGT2B10. SULT, sulfotransferases; UGT,
uridine 50-diphospho-glucuronosyltransferases.
IVERSEN ET AL.7
limit cellular accumulation of endogenous metabolites
and xenobiotics.
70
From our list, P-gp is not categorized as the major
transporter in drug transport of the 100 most used drugs,
but the Top 3 P-gp substrates from our list are atorva-
statin, omeprazole and losartan. P-gp is encoded by the
human multidrug-resistance (MDR1) gene,
71
which is
regulated by two receptors, PXR and CAR.
72
Rifampicin (not on the list) is a well-known inducer of
P-gp, and its impact on P-gp is widely studied with differ-
ent substrates, for example, fexofenadine (number 84).
73
A
clinical study showed that rifampicin decreased area
under the curve (AUC) of fexofenadine by 51%.
73
Verapa-
mil (not on the list) is a well-known P-gp inhibitor, and
coadministration with fexofenadine leads to a 2.5-fold
increase in AUC of fexofenadine in male volunteers.
74
Genetic polymorphisms in MDR1 can potentially alter
the functional expression and activity, but despite extensive
research within this field, there is still no consensus regard-
ing the significance of P-gp genetic polymorphism.
75–77
3.3.2 | Breast cancer resistance protein
(BCRP)
Our review shows that BCRP is known to transport
11 drugs, and besides a substrate overlap of five drugs with
P-gp, BCRP shares substrates of 3–4 drugs with OAT and
MRP1–4(Figure4). Further, BCRP has substrate overlap
with CYP2D6, CYP2C9 and CYP2C19 (1–5 drugs;
Figure 5B). From our list, BCRP is not categorized as the
major transporter in drug transport of the 100 most used
drugs, but The top 3 BCRP substrates from our list are
pantoprazole, furosemide and rosuvastatin.
BCRP is located in, for example, the brain, gastroin-
testinal tract, reproductive organs and muscle tissues.
11,12
A prominent BCRP substrate from our list includes allo-
purinol (number 51). BCRP belongs to the ABC trans-
porter superfamily, and the BCRP transporter is encoded
by the ABCG2 gene.
78,79
BCRP is regulated by AhR, CAR,
PXR, GR, oestrogen receptor β(ER-β), PPAR-γand
nuclear factor erythroid 2-related factor 2 (Nrf2).
80
Febuxostat (not on the list) is a newer xanthine oxi-
dase inhibitor that inhibits BCRP-mediated transport of
rosuvastatin (number 24) both in vitro and in vivo.
81
The
ABCG2 gene is polymorphic, and the ABCG2 c.421C>A
variant is well studied. The minor A allele results in
decreases of 30%–40% BCRP protein expression compared
to the reference allele.
82
A study showed that ABCG2
c.421C>A variant resulted in poor response to the BCRP
substrate allopurinol.
83
Pharmacokinetic data show that
patients carrying the ABCG2 c.421C>A variant have
increased rosuvastatin exposure (144% increased AUC),
which leads to higher risk of myopathy. Furthermore,
genome-wide association studies showed that carriers of
the variant have improved cholesterol-lowering response
of rosuvastatin.
82
Based on these results, the CPIC guide-
line recommends that patients with poor function ABCG2
reduce the starting dose of the BCRP substrate rosuvasta-
tin to ≤20 mg or consider alternative statins if more than
20 mg is needed.
82
3.3.3 | Organic anion transporting
polypeptide 1B1 (OATP1B1) and OATP1B3
OATP1B1 and OATP1B3 are both known to transport
nine drugs. The largest substrate overlap for the two iso-
forms are with each other (eight drugs; Figure 4) and
FIGURE 4 Number of drugs transported by drug transporters
is illustrated with increasing circle size. The size and darkness of
the lines between enzymes illustrate the substrate overlap. Thin/
light-grey line corresponds to 1–2 drugs as substrate overlap.
Medium/grey line corresponds to 3–4 drugs as substrate overlap.
Thick/black line corresponds to >4 drugs as substrate overlap.
Overlap within a group is not illustrated in the figure, but we refer
to Table S1 for further information. The group Other contains
MCT, OATP1A2, OATP4C1, OCTN, LAT, SERT, PMAT, THTR,
CHT, NTCP, PePT and AE. AE, anion exchange protein; BCRP,
breast cancer resistance protein; CHT, choline transporter; LAT,
L-amino acid transporter; MATE, multidrug and toxic compound
extrusion; MCT, monocarboxylate transporter; MRP, multidrug
resistance-associated protein; NTC, sodium-taurocholate co-
transporting polypeptide; OAT, organic anion transporter; OATP,
organic anion transporting polypeptide; OCT, organic cation
transporter; OCTN, organic cation transporter novel; PePT, peptide
transporter; PMAT, plasma membrane monoamine transporter;
P-gp, P-glycoprotein; SERT, serotonin transporter; THTR, thiamine
transporter protein.
8IVERSEN ET AL.
with MRP1–4 (five drugs; Figure 4). OATP1B1 and
OATP1B3 has also substrate overlap of three drugs with
OAT (Figure 4) and substrate overlap with CYP3A4/5,
CYP2C9 and CYP2C19 (1–5 drugs; Figure 5c). OATP1B1
and OATP1B3 are primarily expressed in the liver,
11,12
and they have 80% amino acid homology.
84
From our list,
OATP1B1 and OATP1B3 are not categorized as the major
transporter in drug transport of the 100 most used drugs,
but the Top 3 OATP1B1 and OATP1B3 substrates from
our list are atorvastatin, simvastatin and furosemide.
OATP1B1 and OATP1B3 are members of the solute car-
rier (SLC) family that regulates cellular uptake and is
encoded by SLCO1B1 (OATP1B1) and SLCO1B3
(OATP1B3).
85,86
Both transporters function as active
uptake transporters.
86
The transcriptional regulation of
OATP1B1 and OATP1B3 differ. The major transcriptional
regulators for OATP1B1 are FXR and LXRα, but only
FXR is known to be involved in regulation of
OATP1B3.
87
Rifampicin (not on the list) is an inhibitor of
OATP1B1 and OATP1B3.
88
A study with healthy volun-
teers gave the trial subjects a single dose of rifampicin
and showed a sevenfold increase in AUC of atorvastatin
(number 2), a substrate to OATP1B1 and OATP1B3.
88
The c.521T>C genotype in SLCO1B1 is the most
widely studied polymorphism. This variant leads to
reduced transport activity in vitro.
89
Several studies have
shown that carriers of the c.521T>C genotype are at
increased risk of simvastatin-related myotoxicity (number
5).
90
CPIC guideline states that patients with decreased
or poor function of OATP1B1 are at increased risk of
myopathy upon treatment with atorvastatin and
FIGURE 5 (A) Substrate overlap between
P-gp and CYP3A4/5, CYP2C9, CYP2C19 and
CYP2D6. (B) Substrate overlap between BCRP
and CYP3A4/5, CYP2C9, CYP2C19 and
CYP2D6. (C) Substrate overlap between
OATP1B1/3 and CYP3A4/5, CYP2C9 and
CYP2C19. The size and darkness of the lines
between drug transporter and enzymes illustrate
the substrate overlap. Thin/light-grey line
corresponds to 1–5 drugs as substrate overlap.
Medium/grey line corresponds to 6–10 drugs as
substrate overlap. Thick/black line corresponds
to >10 drugs as substrate overlap. BCRP, breast
cancer resistance protein; CYP, cytochrome P450
enzyme; OATP, organic anion transporting
polypeptide; P-gp, P-glycoprotein.
IVERSEN ET AL.9
simvastatin, and dose should be adjusted accordingly.
82
There is currently no well-validated polymorphism in
OATP1B3 that require altered pharmacotherapy.
4|DISCUSSION
In this review, we identified the 100 most prescribed
drugs in five European countries and Australia. We
found that 89 of the 100 drugs are metabolized either by
Phase I metabolism or Phase II metabolism or are known
to be substrates for drug transporters, whereas 11 drugs
are not subject to drug metabolism or drug transport. In
total, 67 of the 100 drugs undergo Phase I metabolism
where CYP3A4/5 is the predominant enzyme followed by
CYP2D6, CYP2C9, CYP2C19, CYP1A2 and CYP2C8.
UGTs are the most dominant Phase II enzymes responsi-
ble for metabolism of 17 of the 100 drugs. Lastly, P-gp is
the dominant transporter and is known to be responsible
for the transport of 30 of the 100 drugs. CYP3A4/5 and P-
gp share a large substrate overlap of 15 drugs, and if
expression or activity is altered for CYP3A4/5 or P-gp, it
will potentially affect 73 drugs, and this is of substantial
clinical relevance.
A previous study investigated how the 200 most
widely used drugs in the United States are metabolized
through CYP enzymes and found the same five CYP
enzymes to be the major contributors to drug metabo-
lism.
7
A newer and updated version by the same authors
looked at 248 clinically relevant drugs and found that
the contribution of CYP3A4/5 to drug metabolism was
30% and therefore lower compared to their previous
study (37%) and ours (43%).
7,91
Another literature review
described that UGTs are involved in the metabolism of
almost 8% of the 200 most prescribed drugs in the
United States in 2002,
92
which is a smaller contribution
compared to ours at 17%. They also found that UGT2B7
is the most dominant UGT isoform followed by UGT1A4
and UGT1A1.
92
Our update highlights that the latter
two have a minor role today, while UGT2B7 retains its
role as the most important UGT. The methods used to
collect data on drug metabolism from the three previous
articles differ from ours and may impact the results.
Two articles
7,92
retrieved information on elimination
route for the 200 most prescribed drugs through Rxlist.
com. The third article
91
did not describe how the
248 drugs were chosen but found literature on drug
metabolism. Contribution of drug transport to the most
widely prescribed drugs has not previously been investi-
gated. Drug transporters are known to be involved in
the transport of more than half of the most prescribed
drugs and are therefore important to consider in
pharmacotherapy.
In our literature search, we assessed drug metabolism
for each drug. For prodrugs activated through metabo-
lism, drug metabolism covers both the activation route
and the elimination route of the ingested drug. Different
enzymes are responsible for either one of these routes,
and this is important to consider as changes in one of
these enzymes will affect the efficacy differently.
Our updated list is a snapshot of the enzymes and
transporters known to be involved in drug metabolism
and drug transport at the time of data extraction. It
should be noted that pharmacotherapy is constantly
evolving especially regarding Phase II enzymes and drug
transporters, and thus, new knowledge is continuously
obtained. Additionally, new drugs are approved, while
others become obsolete. It is therefore important to
update this list in the future.
The strengths of this review are that we obtained data
on prescription medicine from five countries in Europe
and from Australia, which makes the list applicable for
multiple countries. Furthermore, we used original litera-
ture based on human in vitro studies. We chose human
in vitro studies as these studies are the most accurate to
explain underlying mechanisms for drug metabolism and
drug transport. Additionally, a third author double-
checked our results from the literature search to reduce
the risk of errors. The first limitation to our study is that
we included prescription data from Scotland that were
obtained 6 years ago and thus slightly outdated. Sec-
ondly, two authors each screened articles for 50 drugs
until metabolism and drug transport were confirmed by a
valid article. This could result in slight under-
representation of minor enzyme contributions though we
believe this will be of minor relevance. Thirdly, we
excluded animal studies in our literature search. If the
assessment is performed in animal models or with
murine drug transporters without utilization of human
cell models, it is not included in our literature search.
This might underestimate the contribution of especially
drug transporters as knockout rodent models are widely
used to establish involvement of drug transporters. One
such example is the involvement of OAT3 in ciprofloxa-
cin transport, which was studied in a mouse model
93
but
not caught by our literature search. As this limitation is
only relevant for drugs that are exclusively studied in ani-
mal models, we suspect that there is a relatively low risk
of missing major metabolism and transport pathways.
Fourthly, we were not able to confirm the proportional
contribution (major or minor contribution) of enzymes
and drug transporters to metabolism or drug transport as
conclusive data are not available for most drugs. Fifthly,
we only assessed metabolism and transport of the parent
drug. Thus, we did not cover downstream metabolism
and transport of metabolites. Sixthly, in some countries,
10 IVERSEN ET AL.
drugs are available both as over-the-counter drugs and as
prescriptions, whereas a prescription is required in
others. This could result in slight under-representation of
specific drugs as we only included prescription data.
Finally, we only had prescription data from pharmacies,
while data on medicine used in hospitals were not avail-
able. Thus, drugs primarily prescribed in hospitals were
not included. These may include chemotherapeutic
drugs, biologics, etc.
5|CONCLUSION
In conclusion, we found that 89 of the 100 most pre-
scribed drugs are metabolized and/or known to be trans-
ported. Only 11 drugs are not subject to either drug
metabolism or drug transport. As involvement and over-
lap of enzyme and transporters are high, this study high-
lights the risk of drug–drug interactions in patients
taking multiple medications. Thus, understanding vari-
ability of drug metabolism and drug transport remains a
priority.
ACKNOWLEDGEMENTS
We would like to acknowledge the following for provid-
ing prescription data from Norway, Sweden, Denmark,
Scotland, England and Australia: Øystein Karlstad, Peter
Bjødstrup Jensen, Nicole Pratt and Daniel Morales. The
authors would also like to acknowledge Morten Olsen for
helping with conducting the Top 100 drug list. Further,
we would like to acknowledge Sissel Mogensen for draw-
ing Figure 1.
CONFLICT OF INTEREST
Ann-Cathrine Dalgård Dunvald has given paid lectures
for Astellas Pharma. Tore B. Stage has given paid lectures
for Pfizer and Eisai and done consulting for Pfizer. Anton
Pottegård has participated in research projects funded by
Alcon, Almirall, Astellas, AstraZeneca, Boehringer-
Ingelheim, Novo Nordisk, Servier and LEO Pharma, all
regulator-mandated Phase IV studies. All of this is unre-
lated to the work done in this review. Ditte Bork Iversen
and Nanna Elman Andersen declare that they have no
conflict of interest.
ORCID
Ditte B. Iversen https://orcid.org/0000-0002-5519-9091
Nanna Elman Andersen https://orcid.org/0000-0001-
5750-8911
Ann-Cathrine Dalgård Dunvald https://orcid.org/0000-
0001-7574-0909
Anton Pottegård https://orcid.org/0000-0001-9314-5679
Tore B. Stage https://orcid.org/0000-0002-4698-4389
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article.
How to cite this article: Iversen DB,
Andersen NE, Dalgård Dunvald A-C, Pottegård A,
Stage TB. Drug metabolism and drug transport of
the 100 most prescribed oral drugs. Basic Clin
Pharmacol Toxicol. 2022;1‐14. doi:10.1111/bcpt.
13780
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