We have investigated the effects of
malaria infection with rodent parasite Plasmodium berghei and
fever induced by Escherischia coli
endotoxin on the metabolism of
diazepam to
temazepam by rat liver microsomes, and on the clearance of
ethosuximide in vivo in the rat. Livers from
malaria-infected (parasitaemia =36.8+/- 7.6%
endotoxin-treated or saline-treated (control) rats (N=5 per treatment) were used to prepare microsomes. These were incubated with
diazepam (10-600ū M) for 10 minutes in an
NADPH-generating system. V( max), K(m ) and the intrinsic clearance V(max )/K(m ) for the production of
temazepam were determined. In separate experiments,
ethosuximide (5mg/kg) was administered via the tail vein to control,
malaria-infected and
endotoxin-treated rats (parasitaemia=43.8+/- 5 %) under light
ether anesthesia (N=5 per treatment). Total clearance of ethosuximmide was estimated form a single blood sample obtained 24h after
drug administration.
Diazepam metabolism was not affected by
malaria infection or
fever (V(max ):1.31+/- 0.34,0.73+/- 0.27 and 1.07+/- 0.78 nmol/min/mg
protein; K( m): 158.7 +/- 63.7, 175.3+/- 44.9 and 190.0+/- 81.8ūM; Intrinsic clearance/whole liver: 0.31+/- 0.16, 0.26+/- 0.1 and 0.29+/- 0.1ml/min in livers from control,
malaria-infected and
endotoxin-treated rats respectively; P>0.05). Similarly, clearance of
ethosuximide in vivo was not affected by
malaria infection or
fever (1.3+/- 0.2, 1.3+/- 0.01 and 1.4+/- 0.4 ml/min/kg in control,
malaria-infected and
endotoxin-treated rats respectively; p>0.05). These results suggest that
malaria infection and
fever have no effect on the activities of the
CYP3A isozymes thought to be involved in the metabolism of
diazepam and
ethosuximide.