P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin. We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers. In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism. Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein. This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.

Deposition of the β-amyloid peptide (Aβ) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Aβ is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated in vitro that Aβ40 and Aβ42 interact directly with P-gp. We therefore hypothesized that Aβ accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Aβ, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Aβ40- and Aβ42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 (MDR1) polymorphisms (exon 2, G–1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with MDR1 genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Aβ40 and Aβ42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Aβ may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Aβ from brain.

Objective: We investigated the effect of polymorphisms in the P‐glycoprotein (P‐gp) MDR1 gene on steady‐state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P‐gp expression in the human intestine.Methods: Eight healthy male homozygous carriers of the wild‐type exon‐26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype‐phenotype and haplotype‐phenotype relationships.Results: The area under the plasma concentration‐time curve from time zero to 4 hours [AUC(0–4)] (P = .042) and C_max (P = .043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0–4) (P = .034) and C_max (P = .039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann‐Whitney test) with higher AUC(0–4) values (P = .009) than were found in noncarriers (mean ± SD, 5.7 ± 0.9 μg · h/L [n = 7] versus 4.8 ± 0.9 μg · h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0–4) values (P = .013) compared with those of noncarriers (mean ± SD, 4.7 ± 0.9 μg · h/L [n = 16] versus 5.6 ± 0.9 μg · h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies.Conclusion: Haplotype 12 codes for high values of AUC(0–4) and C_max of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.Clinical Pharmacology & Therapeutics (2002) 72, 584–594; doi: 10.1067/mcp.2002.129196