HEPATOBILIARY AND INTESTINAL CLEARANCE OF AMPHIPHILIC CATIONIC DRUGS IN MICE IN WHICH BOTH MDR1A AND MDR1B GENES HAVE BEEN DISRUPTED

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.