In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(؊͞؊) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(؊͞؊) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2-and 6-fold higher in mdr1a(؊͞؊) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(؊͞؊) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(؊͞؊) mice. Biliary excretion was not significantly different in wt and mdr1a(؊͞؊) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg͞kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(؊͞؊) mice. We conclude that Pglycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.

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Native and chemically derivatized proteins purified from serum and milk were assayed in vitro to assess their inhibiting capacity on the cytopathic effect of human immunodeficiency virus (HIV)-1 and human cytomegalovirus (HCMV) on MT4 cells and fibroblasts, respectively. Only native and conformationally intact lactoferrin from bovine or human milk, colostrum, or serum could completely block HCMV infection (IC50 = 35-100 micrograms/mL). Moreover, native lactoferrin also inhibited the HIV-1-induced cytopathic effect (IC50 = 40 micrograms/mL). When negatively charged groups were added to lactoferrin by succinylation, there was a 4-fold stronger antiviral effect on HIV-1, but the antiviral potency for HCMV infection was mostly decreased. Lactoferrin likely exerts its effect at the level of virus adsorption or penetration (or both), because after HCMV penetrated fibroblasts, the ongoing infection could not be further inhibited.

We have used mice with a disrupted mdrla P‐glycoprotein gene (mdrla (—/—)mice) to study the role of P‐glycoprotein in the pharmacokinetics of digoxin, a model P‐glycoprotein substrate. [3H]‐digoxin at a dose of 0.2 mg kg−1 was administered as a single i.v. or oral bolus injection. We focussed on intestinal mucosa and brain endothelial cells, two major pharmacological barriers, as the mdrla P‐glycoprotein is the only P‐glycoprotein normally present in these tissues. Predominant faecal excretion of [3H]‐digoxin in wild‐type mice shifted towards predominantly urinary excretion in mdrla (—/—) mice. After interruption of the biliary excretion into the intestine, we found a substantial excretion of [3H]‐digoxin via the gut mucosa in wild‐type mice (16% of administered dose over 90 min). This was only 2% in mdrla (—/—) mice. Biliary excretion of [3H]‐digoxin was not dramatically decreased (24% in wild‐type mice versus 16% in mdrla (—/—) mice). After a single bolus injection, brain levels of [3H]‐digoxin in wild‐type mice remained very low, whereas in mdrla (—/—) mice these levels continuously increased over a period of 3 days, resulting in a ∼200 fold higher concentration than in wild‐type mice. These data demonstrate the in vivo contribution of intestinal P‐glycoprotein to direct elimination of [3H]‐digoxin from the systemic circulation and to the pattern of [3H]‐digoxin disposition, and they underline the importance of P‐glycoprotein for the blood‐brain barrier.