Biomedical Engineering Reference
In-Depth Information
Q
r
f
p
CL
r
,int
Q
r
+
f
p
CL
r
,int
CL
sec
CL
renal
= (1− ER)
f
p
× GFR
+
Assumption
CL
renal
~CL
r,int
~CL
int,uptake
, ER
=
constant
In vivo
clinical data
(cited from ref. 84)
CL
renal
[mL/min]
CL
sec
[mL/min]
observed
CL
sec
(
probenecid)
CL
sec
(− probenecid)
= 0.112
+
−
probenecid
+
probenecid
297
+
19
196
+
21
−
107
+
5
−
−
22.0
+
4.2
−
Maximum protein unbound concentration of
probenecid
=
20 ~ 50
μ
M
predicted
1
I
in,max
In vitro
inhibition assay (cited from [84])
R
=
1
= 0.049 ~ 0.113
Inhibitory effect of probenecid on hOAT3-
mediated uptake of famotidine K
i
=
2.55
μ
M
+
K
i
FIGURE 19.9.
Prediction of the drug-drug interaction between famotidine and probenecid
in humans from in vitro data. Renal clearance (CL
renal
) is described by this equation. ER,
reabsorption ratio;
Q
r
, renal blood flow;
f
p
, plasma protein unbound fraction; CL
r
,
int
, intrinsic
secretion clearance; GFR, glomerular filtration rate. Based on the pharmacokinetic parameters,
renal clearance can be approximated by CL
r
,
int
in this case, and assuming that renal uptake
is the rate-determining process of overall renal secretion, CL
r
,
int
is thought to be equal to
intrinsic uptake clearance (CL
int, uptake
). The extent of decrease in the renal secretion clearance
in the clinical study was well predicted from the information of the maximum protein unbound
concentration of probenecid in the clinical study and the
K
i
value of probenecid for the human
OAT3-mediated uptake of famotidine. (From ref. 84.)
and the inhibition of OAT3-mediated uptake of famotidine by probenecid causes a
drug-drug interaction (Figure 19.9).
Tahara et al. also examined the interspecies differences in the transport activities of
OAT1 and OAT3 in rats, monkeys, and humans using gene expression systems.
85
In the
case of OAT1-mediated uptake, a good correlation of the relative uptake clearances of
11 compounds was observed between humans and monkeys and between humans and
rats. On the other hand, the relative clearances of nine substrates mediated by human
OAT3 did not correlate well with those mediated by rat Oat3. They also showed
that the tubular secretion clearance of famotidine was reduced to one-tenth when
coadministered with probenecid, and the drug-drug interaction between famotidine
and probenecid was observed in both monkeys and humans.
86
Moreover, OCT1 is
not expressed in monkey kidney. These results suggest that the monkey is a more
appropriate animal model for predicting OAT3-mediated drug-drug interactions.
Nozaki et al. have examined the contribution of transporters [Oat1, Oat3, and
reduced folate carrier (RFC)-1] to the overall renal uptake of methotrexate and
the inhibitory effects of several nonsteroidal anti-inflammatory drugs (NSAIDs)
on the transporter-mediated uptake of methotrexate to investigate the mechanism
of the drug-drug interaction between methotrexate and NSAIDs.
87
The uptake of
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