Pharmacological Approach to Combat Mosquito Transmitted Malaria

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proteins. The contribution of malaria to the volume of distribution of lumefantrine and

artemether is still an area for research.

There is significant first pass metabolism of orally administered lumefantrine and

artemether. Lumefantrine is excreted unchanged through the bile as well as desbutylated

metabolite, that is rapidly excreted. The elimination of artemether is through metabolism

mainly by CYP3A4 and CYP3A5 liver enzymes, that also catalyzes the metabolism of

lumefantrine. The main metabolite of artemether is dihydroartemether (DHA) and it is an

active metabolite with antimalarial activity. DHA is further glucuronidated and excreted

through bile. The role of CYP3A4 in the metabolism of both lumefantrine and artemether

means there is potential for drug interactions with inhibitors and inducers of CYP3A4,

such as ketoconazole and antiretrovirals. Lumefantrine is also an inhibitor of CYP2D6.

Finally, the clearance (Cl) is estimated by using the formula:

Cl = K10 ×Vc

(10.8)

Since both lumefantrine and artemether are eliminated predominantly by the liver, which

is part of the central compartment, Cl is related to elimination half-life (t½) as follows:

t1/2 = ^0,693Vc

Cl

(10.9)

The elimination half-life for of lumefantrine is 3 to 4 days and artemether is between 1

to 3 hours [25] thus lumefantrine easily accumulates to higher levels in the body and per-

sists longer than artemether producing effect for longer time after administration. The inhi-

bition of CYP3A4 has been associated with a decrease in the clearance of lumefantrine and

artemether. Inhibitors of CYP3A4 significantly decrease the clearance (Cl) of artemether

by 70 percent. There interindividual variations in Cl are seen with body weight, age and

height. The potential for clinically significant interaction is always there, therefore caution

is emphasized when using drugs that are known to be metabolized by CYP2D6 and induce

or inhibit CYP3A4 [21].

10.5

TREATMENT OF PREGNANT WOMEN

When a woman becomes pregnant, her physiology start to adjust to the new condition.

These factors will affect the pharmacokinetics of the drugs. This can be shown graphi-

cally in (10.4), with the appearance of a new compartments. Among these physiological

changes, that are affected by pregnancies and will impact the pharmacokinetics of drugs,

are the cardiovascular system, the liver and the renal excretion, just to mention few exam-

ples. The portal vein blood flow is increased from 1.25 L/min to 1.92 L/min and the hepatic

artery blood flow is increased from 0.57 L/min to 1.06 L/min [26]. Similarly, glomerular

filtration rate is increased from 97 mL/min to 144 mL/min [27]. Plasma volume is also

increased from 2.6 L to about 3.5 L [28]. The ratio of liver enzymes is also changed across

gestation, such as CYP3A4, that goes from 73% in non-pregnant women, to 75%, 80% and

83% in weeks 10, 20 and 30, respectively. Other enzymes may decrease such as CYP2B6

that are found in 9%, 8%, 6% and 6% in weeks 0, 10, 20 and 30, respectively [29].