j. antimicrob. chemother. 2008 sousa 872 8 (1)

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Pharmacokinetics and pharmacodynamics of drug interactionsinvolving rifampicin, rifabutin and antimalarial drugs

Marta Sousa1,2, Anton Pozniak1 and Marta Boffito1*

1St Stephens Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK;2Centro Hospitalar de Vila Nova de Gaia, Portugal

Malaria and tuberculosis (TB) are two major global diseases mostly affecting the developing countries.

Their treatment is often complex because of the drugs used, multidrug resistance, drug interactions

and logistic problems such as drug availability and access. Patients are treated for TB for a minimum

of 6 months and may concomitantly develop and be treated for malaria, especially during the rainy

season. Rifampicin, a standard component of combination regimens for treating TB, is a potent

inducer of hepatic cytochrome and other metabolic enzymes and is able to influence the pharmaco-

kinetics of many drugs. Rifabutin, another rifamycin used less frequently than rifampicin, can alsointeract with drugs metabolized through the hepatic cytochromes. The mechanisms of any interaction

of rifamycins with drugs used in malaria are not well defined. To complicate matters, acute malaria

also plays a role in the pharmacokinetics and pharmacodynamics of drugs (i.e. quinine). The aim of

this paper is to review known and potential drugdrug interactions between rifampicin, rifabutin and

antimalarial drugs.

Keywords: treatment of malaria, tuberculosis, pharmacology of antimalarial agents

Introduction

Malaria and tuberculosis (TB) are endemic diseases in manycountries with limited resources and are frequently found at the

same time. Together, they kill more than 3 million people each

year.1

These diseases have a synergic negative effect on public

health and are considered to be great barriers to economic devel-

opment. The relationship of these diseases with HIV and the

problems of drug resistance are major causes of concern, and

they adversely affect morbidity and mortality.1

The co-existence of these two diseases leads to various con-

cerns about their treatment. For several reasons, simultaneous

malaria and TB treatment poses many challenges. One of these

is the potential for drug drug interactions between the most

commonly used drugs. Rifampicin, a standard component of

combination regimens for treating TB, is a potent inducer of

hepatic metabolism and is able to influence the pharmaco-kinetics of several drugs. Rifabutin, another rifamycin used less

frequently than rifampicin, can also interact with drugs meta-

bolized through the hepatic cytochromes. The drugdrug inter-

actions of rifamycins and most drugs used in malaria are not

well defined. Moreover, acute malaria itself can influence the

pharmacokinetics and pharmacodynamics of different drugs by

influencing liver metabolism, binding to plasma proteins and

excretion by mechanisms that remain unclear.2

The aim of this paper is to review known and potential

drug drug interactions between rifampicin, rifabutin and anti-

malarial agents.

Pharmacokinetics, pharmacodynamics and drug

interactions

Pharmacokinetics studies the absorption, distribution, meta-

bolism and excretion of a drug, and pharmacodynamics studies

the relationship between the drug and its receptors, its mechan-

ism of action and therapeutic effect. Both can play a role in

drugdrug interactions.

Many drugs share the same metabolic pathways or target the

same receptors. This leads to the occurrence of pharmacokinetic

and pharmacodynamic differences, respectively. Drug druginteractions occur mainly during drug absorption, distribution

(plasma drug binding protein), biotransformation and excretion.

Most drugs are given by the oral route. Subsequently, absorp-

tion is mostly through the intestinal mucosa (duodenum). Drug

bioavailability is dependent on an enterocyte P-glycoprotein,

which can actively pump back drugs into the intestinal lumen,

and on enterocyte cytochrome P450 (CYP450) enzymes, meta-

bolizing the drug before it reaches the systemic circulation.3

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

*Corresponding author. Tel: 44-20-8846-6507; Fax: 44-20-8746-5628; E-mail: [email protected]

Journal of Antimicrobial Chemotherapy (2008) 62, 872 878

doi:10.1093/jac/dkn330

Advance Access publication 18 August 2008

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Induction or inhibition of P-glycoprotein and enterocyte

CYP450 can thus influence drug bioavailability. After being

absorbed, drugs generally bind to plasma transport proteins

(i.e. albumin, a-1-acid-glycoprotein). The level of binding

protein plays a fundamental role in distribution and various

drugs can affect protein binding. When the drug passes through

the liver, it is metabolized to active and/or non-active meta-

bolites. This is called biotransformation and this has a great

influence on therapeutic efficacy. Drug biotransformation isdependent on several phases. Phase I consists of hydrolysis, oxi-

dation and reduction, which is mediated mostly by CYP450.4,5

Phase II consists of conjugation and is mediated by enzymes

such as uridine diphosphoglucuronosyl transferase, N-acetyl

transferase and glutathione S-transferase. These enzymes play an

important role in the detoxification and/or excretion rate of

xenobiotics.5,6

Phase III is mediated by drug plasma membrane

transporters (influx and efflux), such as P-glycoprotein, multi-

drug resistance protein (MRP) and organic anion transport

protein 2 (OATP2), that are localized in the liver on the endo-

thelium and epithelium membrane, as well as in the gastrointes-

tinal tract, kidney and other organs. They play an important role

in drug pharmacokinetics and pharmacodynamics. In the liver,

OATP1 and OATP2 are localized in sinusoidal phase membraneof hepatocytes and are responsible for the uptake of many drugs

to be metabolized.7

MRP2 and P-glycoprotein are localized in

the canalicular phase membrane of the hepatocytes and are

responsible for pumping out xenobiotics (i.e. drugs and their

metabolites) to the biliary canals.7,8

Since they are present in

several types of cells, and mediate cell exposure to drugs, they

can influence not only absorption, distribution, metabolism and

elimination, but also drug concentrations inside the target cell

and affect the therapeutic efficacy.5

Acute malaria itself has been shown to influence the metabolism

and distribution of certain drugs not, it seems, by influencing drug

absorption but by increasing binding to a-1-glycoprotein in

plasma.2

Inhibition of hepatic metabolism, mainly CYP3A4

enzymes in acute malaria, leads to a reduced clearance of quinine.9

Rifampicin and rifabutin pharmacokinetics

Both rifampicin and rifabutin are drugs used for the treatment of

TB. Rifampicin is derived from rifampicin B that is produced

by Streptomyces mediterranei and has been in use since 1965.

Rifabutin is derived from rifamycin S and is mostly used in HIV

co-infected patients because it has fewer drug interactions with

antiretroviral agents (i.e. protease inhibitors) than rifampicin.

It is also used in atypical mycobacterial infections and, in some

cases, it has been shown to be active when there is rifamycin

resistance.1012

Both drugs act by inhibiting the b-subunit-dependent DNA RNA polymerase that leads to suppression

of DNA formation by Mycobacterium tuberculosis. They are

bactericidal and bacteriostatic and act intra- and extracellularly.

Absorption

Both drugs are generally well absorbed by the oral route.

Altered absorption, however, has been observed in patients

with AIDS, diabetes and gastrointestinal diseases. Furthermore,

pharmacokinetic studies show a high inter-individual variability

of rifampicin absorption characterized by slow and fast absorp-

tion patterns.13

Distribution

Rifampicin is highly lipophilic, it is 80% bound to plasma

proteins, mainly a-1-acid-glycoprotein,14

and it is characterized

by a plasma half-life of 2 5 h. Rifabutin is 85% bound to

plasma proteins in a concentration-independent manner. Due totheir high lipophilicity, both demonstrate a high propensity for

distribution and intracellular tissue uptake.

Biotransformation

Rifampicin is deacetylated by hepatic microsomal enzymes, and

it is also a great CYP450 inducer, the most potent inducer of all

drugs used in clinical practice. This leads to decreased drug con-

centrations by an autoinduction mechanism, whereby the drug

stimulates its own metabolism into inactive metabolites.15

It undergoes progressive enterohepatic circulation and deacetyl-

ation to the primary active metabolite, 25-desacetyl-rifampicin.

Rifabutin is metabolized by CYP3A.

16

Of the five meta-bolites that have been identified, 25-O-desacetyl and 31-hydroxy

are the most predominant. The former has an activity equal to

the parent drug and contributes up to 10% of the total antimicro-

bial activity.13,17

Excretion

Rifampicin is rapidly eliminated mainly in the bile. Up to 30%

is excreted in urine. Rifabutin is mostly excreted in urine, pri-

marily as metabolites. About 30% of the dose is excreted in the

faeces.13,17

Enzyme induction and inhibitionBecause of the influence on the liver metabolic activity, rifam-

picin has been shown to be involved in several drugdrug

interactions.

Rifampicin is an N-acetyltransferase inhibitor and leads to a

decrease in the acetylation ratio in fast acetylators. However, the

most important mechanism behind rifampicin drug interactions

is its potent inducing effect on hepatic and intestinal CYP450

enzyme activity (CYP3A4, CYP1A2, CYP2C9, CYP2C8 and

CYP2C18/19).5,18

Moreover, rifampicin has an important role in hepatic drug

uptake and gastrointestinal absorption of drugs as it is a

P-glycoprotein,8,18,19

an MRP,20

a transport system inducer and

an OATP2 inhibitor.8,18

Based on tissue distribution of these

membrane transporters, modulation of their activity may result

in significant alterations in the pharmacokinetics and, poten-

tially, the pharmacodynamics of several drugs.

The mechanism of rifampicin induction of CYP enzymes is

mediated by the activation of nuclear pregnane X receptor

(PXR), a member of the nuclear receptor superfamily. A recent

study performed in mice demonstrated that CYP3A4 is

dysregulated in PXR-null mice, confirming that PXR transcrip-

tionally regulates CYP3A4.21,22

PXR binds to CYP3A promoters

to activate reporter genes. PXR also up-regulates other Phase I,

II and III enzyme genes,21

such as MDR1, a gene encoding

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P-glycoprotein. Rifampicin is a PXR ligand and activates tran-

scription of CYP3A4 and other proteins such as P-glycoprotein.

Another receptor, constitutive androstane receptor (CAR), is

also involved in CYP3A4 transcriptional regulation, but rifam-

picin has a lesser effect on CAR than on PXR.

Rifampicin is responsible for broad changes in the pattern of

gene expression, rather than increased expression of a small

number of metabolic enzymes. Clinicians should be alert to the

possibility of its multiple effects.23

Rifabutin induces CYP3A and may reduce the plasma concen-

trations of drugs that are mostly metabolized by this enzyme.

However, rifabutin is a weaker enzyme inducer than rifampicin.24

Importantly, rifabutin is also a substrate of CYP3A4. Therefore,

its concentrations may be altered during co-administration with

CYP3A4 inducers and inhibitors and dose adjustments may be

required.

Antimalarial drugs

Malaria treatment is far from simple. Resistance to chloroquine

is widespread, and resistance to other agents and multidrug

resistance is emerging in many countries.

There are 15002000 cases of imported malaria reported in

the UK each year and 10 20 deaths. Approximately three-

quarters of reported malaria cases in the UK are caused by

Plasmodium falciparum.25

In 2002, 1337 cases of malaria were

reported in the USA; all but five were imported.26

The success

of malaria treatment is dependent on knowledge of the current

malaria resistance patterns of the areas where the patient was

infected.

Quinine

Quinine is one of the most commonly used drugs for malaria

treatment worldwide. It is the first-line treatment for P. falciparumcomplicated malaria and is a treatment option for P. falciparum

uncomplicated malaria in chloroquine-resistant regions.2527

Quinine seems to act against Plasmodium spp. by inhibiting haem

polymerase that leads to toxic haem levels.27

Quinine metabolism

is interesting because acute malaria influences absorption, the

binding-protein fraction, CYP450 activity and excretion of

quinine. Pukrittayakamee et al.9

studied patients with severe

malaria to assess the factors that could influence the decreased

clearance of quinine and concluded that the most important factor

was the impairment of CYP3A function.

Biotransformation. In acute malaria, 78% to 95% of quinine is

bound to a-1-acid-glycoprotein.2

It is metabolized almost

exclusively via CYP450, mostly by CYP3A4,28

and CYP2C19.The metabolism of quinine is not completely understood but

CYP1A2 and CYP2D6 may also have a role.29,30

One of its

metabolites is 3-hydroxyquinine, which is important as it has

10% of the activity of the parent drug.29

Excretion. Quinine is mostly eliminated via the hepatic route,

and 20% of it is excreted unchanged in the urine.

Enzyme induction and inhibition. Quinine inhibits the activity of

CYP2D631

and inhibits P-glycoprotein32

and biliary excretion.

Therefore, it has an important role in the elimination of several

drugs.

Drug interactions. There is evidence that rifampicin may have

antimalarial activity in humans.33,34

The antimalarial mechanism

of rifampicin may be similar to that observed in TB. The target

of rifampicin may be the Plasmodium organellar circular DNA

molecule that encodes the b-subunit of a prokaryocyte-like RNA

polymerase.29,35

Both quinine and rifampicin influence several steps in drug

metabolism and distribution.

Enterocyte P-glycoprotein activity is inhibited by quinine and

induced by rifampicin.3

Rifampicin also induces enterocyte

CYP3A. Overall, in theory, this could lead to a decrease in bio-

availability of quinine.

In plasma, both rifampicin and quinine are bound to

a-1-acid-glycoprotein. Acute malaria, TB14

and rifampicin

administration36

increase a-1-acid-glycoprotein levels, and this

could influence quinine distribution, metabolism and efficacy.

The OATP system is responsible for quinine hepatic uptake

and rifampicin is an OATP inhibitor7,8,18

and could therefore

theoretically influence quinine concentrations. Moreover, by

inhibiting P-glycoprotein, quinine inhibits biliary excretion7 andmay theoretically alter rifampicin half-life.

Several in vivo studies have been performed to investigate the

interactions between quinine and rifampicin. Wanwimolruk

et al.37

studied the effect of 1 week pre-treatment with rifam-

picin (and isoniazid) on quinine pharmacokinetics in healthy

volunteers. They showed that the mean clearance of quinine was

significantly greater (0.87 versus 0.14 L/h/kg) and the mean

elimination half-life of quinine was shorter with rifampicin

pre-treatment than when quinine was given alone (5.5 versus

11.1 h).

Pukrittayakamee et al.29

studied the effect of combined

therapy (rifampicin and quinine) in patients with acute uncom-

plicated P. falciparum malaria. Interestingly, they observed that

the parasite clearance was faster with the combination. Thiscould be because of the rifampicin antimalarial effect rather

than a drug interaction as rifampicin can take several days to

induce CYP3A4 activity that is responsible for quinine meta-

bolism. After the second day of rifampicin treatment, quinine

pre-dose plasma concentrations decreased progressively through-

out the treatment period, leading to a fall in quinine activity that

may have been the reason for a malaria recrudescence rate five

times higher in this group. The authors concluded that, although

rifampicin could have therapeutic effects in malaria, the drugs

should not be combined to treat malaria. In those patients who

are already on rifampicin for the treatment of TB, quinine doses

must be increased. However, no advice on dose-adjustment strat-

egies has been provided and quinine therapeutic drug monitoring

has been suggested to be useful to guide dosing.

Cerebral malaria is the commonest cause of non-traumatic

encephalopathy in the world. The standard treatment is with

quinine. Quinine penetrates relatively poorly into the cerebro-

spinal fluid (CSF) in patients with cerebral malaria, with a con-

centration approximately 2% to 7% of that measured in plasma.

P-glycoprotein is one of the blood brain barrier (BBB) mem-

brane transporters and modulates central nervous system (CNS)

drug exposure, playing an important role in preventing CNS

drug accumulation. Reducing P-glycoprotein activity dramati-

cally increases the penetration of many therapeutic drugs into

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the CNS. Studies in rats have shown that brain capillary

P-glycoprotein is transcriptionally up-regulated by the PXR, and as

rifampicin is a PXR ligand, it increases P-glycoprotein expression

in the BBB.38

Therefore, the co-administration of rifampicin

and quinine could decrease quinine concentrations in the CSF.

However, whether this compromises drug efficacy remains

unclear, as the clinically relevant concentrations of quinine are

those measured in the systemic circulation, where parasitized

erythrocytes remain.Despite being a less potent CYP3A4 inducer than rifampicin,

rifabutin and quinine should also be cautiously co-administered

as both drugs use the same metabolic pathways. Nevertheless,

no data are available on the potential interaction between

rifabutin and quinine.

Chloroquine

Despite the worldwide spread of P. falciparum resistance to

chloroquine, this drug is still used as a first-line treatment for

Plasmodium ovale, Plasmodium malariae and Plasmodium

vivax in regions where there is no known resistance.

The mechanism of plasmodicidal action of chloroquine is not

completely certain. It is thought to inhibit the haem polymeraseof Plasmodium, increasing haem to toxic levels. Chloroquine is

almost completely absorbed when given by the oral route. It

binds to plasma proteins, and it is metabolized in the liver

by CYP450 (mainly CYP2C8 and CYP3A4/5)39

to desethyl-

chloroquine, which has an activity similar to chloroquine, and

bisdesethylchloroquine. The MRP membrane transport system is

responsible for chloroquine cellular efflux and may be the

mechanism implicated in the development of resistance to

chloroquine. There are several in vitro studies suggesting that

P. falciparum chloroquine resistance may be reversed with

P-glycoprotein inhibitors such as roxithromycin40

or fluoxe-

tine.41

Importantly, despite reporting that the observed effect

occurred at clinically achievable concentrations, the difference

in drug protein binding between the in vitro and in vivo systemsmay lead to remarkable differences between the two environ-

ments. Similar findings, however, have been observed both

in vitro and in vivo with calcium channel blockers (i.e. verapamil).

These showed effectiveness against chloroquine-resistant

P. falciparum by increasing chloroquine accumulation inside the

food vacuole.42

One study in infected mice reported that the combination of

rifampicin and chloroquine decreased their survival rate and the

rate of clearance of parasitaemia and increased the rate of recru-

descence.43

The decrease in chloroquine efficacy when admini-

strated in combination with rifampicin may be due to the

inducing effect of rifampicin on MRP20

and on CYP450

activity. Concomitant use of these drugs might have to be

avoided; however, data in humans are lacking.

Studies are needed to explore drugdrug interactions

between rifabutin and chloroquine as there are no data regarding

this interaction.

Atovaquone and proguanil

Atovaquone, combined with proguanil, is a treatment option for

P. vivax infection. It is also used for malaria prophylaxis.

Its activity against Plasmodium is due to the inhibition of mito-

chondrial electron transport.27

Atovaquone is 99% bound to

plasma proteins and has a 70 h half-life. It is characterized by an

enterohepatic circulation, is metabolized in the liver and is mostly

excreted unchanged in the faeces. There is in vitro evidence of

possible inhibition of CYP3A4 by atovaquone,44

and studies that

used atovaquone in the treatment of Toxoplasma gondii showed

that atovaquone area under the curve (AUC) decreased remark-

ably (50%) when combined with rifampicin but not as much

(34%) with rifabutin.44

The concomitant administration of atova-

quone and rifampicin is therefore not recommended, while theclinical significance of the moderate decrease in atovaquone con-

centrations in the presence of rifabutin remains unclear.

Moreover, despite the lack of studies on rifabutin and atova-

quone in malaria, there are several studies on their co-administration

for the treatment of opportunistic infections. This combination

seems to have a synergistic effect in the prophylaxis of

Pneumocystis jiroveci pneumonia and T. gondii in mice.45

Proguanil is used in combination with atovaquone and should

not be used alone because resistance to it develops very

quickly.27

Seventy-five percent of the drug is bound to plasma

proteins, and it undergoes bioactivation by CYP2C19 to the

active metabolite, cycloguanil. Cycloguanil inhibits plasmodial

dihydrofolate reductase and influences DNA synthesis.

Since rifampicin is a potent inducer of CYP2C19, it is poss-ible that it could affect proguanil antimalarial activity.

Data on this interaction are unavailable and further studies

are needed to clarify the effect of rifampicin and rifabutin on

proguanil pharmacokinetics and efficacy.

Mefloquine

Mefloquine is an antimalarial agent used for the treatment and

prophylaxis of chloroquine-resistant P. falciparum and non-

falciparum malaria. It is also often used in combination with

artemisinins. Its exact mechanism of action is not known. After

absorption, it binds almost completely to plasma proteins and is

metabolized by CYP3A into two inactive metabolites.

46

It isknown that the pharmacokinetics of mefloquine is altered in

acute malaria.47

Just like chloroquine, mefloquine resistance seems to be

mediated by MDR transport system activity,48 which can be

increased by rifampicin. Furthermore, rifampicin induces meflo-

quine metabolism,46

decreasing its AUC by 68% and half-life

by 63%.49

Importantly, mefloquine metabolite AUC and clear-

ance increased by 30% and 25%, respectively. These changes

did not reach a statistical significance. The authors suggested

avoiding simultaneous administration of mefloquine and rifampi-

cin on the basis of these pharmacokinetic findings. However, no

data are available on the clinical efficacy of this combination.

In 1999, Bermudez et al.50

found that mefloquine has in vitro

and in vivo activity against Mycobacterium avium complexincluding strains with multidrug resistance. More studies are

needed to further increase our knowledge about mefloquine

pharmacodynamics and drug interactions with rifabutin and

rifampicin.

Artemisinins

Artemisinins and their derivates (i.e. artemether and artesunate)

are drugs recently developed to treat malaria. The advantages of

these drugs are the antimalarial effect against P. falciparum

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gametocytes (previously only susceptible to primaquine) and the

lack of evidence of resistance to these agents to date.

Artemether did not prove to be better than quinine on survi-

val rate,51

and artesunate is the first choice in low-transmission

areas. These drugs should be given in combination therapy with

other antimalarial agents (i.e. mefloquine) since better parasite

clearance rates have been observed compared with monother-

apy.52

High efficacy of two artemisinin-based combinations

(artesunate plus amodiaquine and artemether plus lumefantrine)has been shown over the past few years in areas where TB is

endemic.53

The clinical pharmacology of artemisinin-based combination

therapies is highly complex. All artemisinin compounds are

metabolized by CYP3A454

to the active compound dihydroarte-

misinin, also available as a drug in itself. They also seem to

induce CYP2C19 activity and their own metabolism.54,55

There

are no studies looking at the concomitant administration of

artemisinins and rifampicin or rifabutin. However, theoretically,

drug interactions may occur because of the inducing effect of

rifampicin and rifabutin on different CYP450 enzymes, leading

to a more extensive time-dependent decline in drug plasma con-

centrations and hypothetical decrease in efficacy.

Amodiaquine and lumefantrine are metabolized by CYP2C856

and 3A4,57

respectively, and may be theoretically decreased

by rifampicin or rifabutin co-administration. Pharmacokinetic/

pharmacodynamic investigations to investigate the interaction

between artemether/lumefantrine (Coartemw

) and rifampicin are

currently being conducted at the University of Makerere, Kampala,

Uganda (clinicaltrials.gv NCT00620438; Dr Mohammed Lamorde,

personal communication).

Primaquine

Primaquine is used to provide a cure for P. vivax and P. ovale

malaria, and it is also gametocytocidal against P. falciparum.

The mechanism of action is unknown.27

It is metabolized in the

liver by CYP450 enzymes, possibly CYP3A4.58,59 Therefore,co-administration of primaquine and rifampicin or rifabutin

may influence the pharmacokinetics of primaquine and alter

its plasma concentration. However, there are no data on this

potential interaction.

Doxycycline and clindamycin

Doxycycline is a tetracycline derivative that is used in malaria

treatment in combination with quinine to ensure cure.25,29,60 It is

an inhibitor of protein synthetase by disrupting messenger RNA

and transfer RNA; 80% to 95% binds to plasma proteins and is

metabolized in the liver by an unknown mechanism. No meta-

bolites have been identified to date.61

Sixty percent is excreted

in the faeces and 40% in the urine. Hepatic inducers such as

rifampicin, and probably rifabutin, accelerate its metabolism and

influence its plasma exposure (doxycycline AUC and half-life

decreased by 40% with rifampicin).62

However, whether drug

efficacy is compromised remains unclear.

Clindamycin is a lincosamide antibiotic that inhibits early

stages of protein synthesis at the ribosome level. It is used

in malaria treatment as a valid alternative to doxycycline in

pregnant women. Ninety percent is bound to plasma proteins.

It is metabolized in the liver by CYP3A enzymes,63

to several

active and inactive metabolites that are excreted in the faeces.

Clindamycin is a moderate inhibitor of CYP3A in vitro, and

the potential for drug drug interactions involving clindamycin

is low.63

However, rifampicin induces CYP3A4 and could

theoretically induce clindamycin metabolism and decrease its

half-life. These drugs should be co-administered cautiously.

Conclusions

Malaria and TB are two diseases that are often found concomi-

tantly in developing countries and can have a synergic negative

effect on public health. In developed countries almost all cases

of malaria are imported, but TB still has a high prevalence in

some European countries, especially associated with HIV infec-

tion. Treatment of these two diseases leads to several concerns

about drug drug interactions and the potential for inducing drug

resistance.

Rifampicin, a standard component of combination regimens for

treating TB, has a great influence on the bioavailability and the

efficacy of several drugs, not only because of the inhibition of

Phase I and II enzymes of hepatic metabolism, but also because of

its effect on drug absorption and distribution. It induces almost all

CYP450 enzymes, it inhibits N-acetyltransferases and it alters theexpression of membrane transporters. Rifampicin induces intesti-

nal, BBB and hepatic P-glycoprotein and MRP expression, and it

inhibits OATP2. Most of these inducing effects are due to PXR-

increased transcription; therefore, understanding each individuals

genotype is important to explain the several unknown mechanisms

behind these complex drugdrug interactions. Rifabutin is mostly

used in HIV co-infected patients because it has fewer drugdrug

interactions with antiretroviral agents. Although rifabutin is a

weaker CYP3A4 enzyme inducer than rifampicin, it may be

expected to have some effect on drug metabolism as well. In

many cases, the interactions between rifampicin or rifabutin and

antimalarial agents are likely but not studied and confirmed.

Moreover, the consequences of simultaneous malaria and TB

treatment are not well known. In each case, the need for conco-

mitant treatment should be carefully considered, since malaria is

an acute disease and TB is a subacute disease. There are a large

number of drug mechanisms that need to be explored concerning

antimalarial drug activity. These may be vital to treat TB and

malaria simultaneously where multidrug resistance in both

diseases is common.

Transparency declarations

Conflicts of interest: none to declare.

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