Jw. Smit et al., HEPATOBILIARY AND INTESTINAL CLEARANCE OF AMPHIPHILIC CATIONIC DRUGS IN MICE IN WHICH BOTH MDR1A AND MDR1B GENES HAVE BEEN DISRUPTED, British Journal of Pharmacology, 124(2), 1998, pp. 416-424
1 We have used mice with homozygously disrupted mdr1a and mdr1b genes
(mdr1a/1b (-/-) mice) to study the role of the mdr1-type beta-glycopro
tein (P-gp) in the elimination of cationic amphiphilic compounds from
the body. These mice lack drug-transporting P-gps, but show no physiol
ogical abnormalities under laboratory conditions and have normal bile
flow. 2 H-3-labelled cationic drugs were administered intravenously (i
.v.) to mice as a single bolus dose and the disposition of the studied
cationic drugs was investigated by focusing on drug secretion into bi
le, intestinal lumen and urine. 3 Hepatobiliary secretion of the inves
tigated cationic drugs was profoundly reduced in mice devoid of the md
r1-type P-gps. In fact, the cumulative biliary output, measured during
1 h, of the small type I compounds tri-butylmethyl ammonium (TBuMA) a
nd azidoprocainamide methoiodide (APM), as well as of the more bulky t
ype 2 cationic drug vecuronium, was reduced by at least 70% in the mdr
1a/1b (-/-) mice compared to wild-type. 4 The intestinal secretion of
TBuMA, APM and vecuronium was also profoundly reduced in mdr1a/1b (-/-
) mice compared to wild-type mice. The absence of the mdr1-type P-gp r
esulted in virtual elimination of intestinal secretion of TBuMA and AP
M (>90% reduced as compared to wild-type (P = 0.0001 and 0.0022, respe
ctively)). The intestinal secretion of the type 2 cation drug vecuroni
um was reduced by 58% (P = 0.0004) compared to the wild-type mice. 5 I
ncreased renal clearances of both the type 1 compounds TBuMA and APM a
nd also of the type 2 cationic compound vecuronium in the mdr1a/1b (-/
-) mice were observed. Furthermore, the balance between hepatic, intes
tinal and renal clearances of small type 1 organic cations clearly shi
fted towards a predominant role for renal clearance. Increased renal c
learance may be explained by (over)expresion of additional mechanisms
for renal organic cation secretion, alternatively they may also point
to an as yet undefined role of P-glycoprotein in kidney physiology and
renal secretory function. 6 We conclude that the elimination from the
body of a broad spectrum of cationic amphiphilic drugs via liver and
intestine, is largely dictated by the activity of mdr1-type P-glycopro
teins.