Certain commonly occurring single-nucleotide polymorphisms in OATP-C, such as T521C (Val174Ala), are likely to be associated with altered pharmacokinetics of pravastatin. Large clinical studies are needed to confirm these observations.
ABSTRACT:The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-singlestrand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency.Breast cancer resistance protein (BCRP), also called mitoxantroneresistant protein, is the second member of the G family of ATPbinding cassette transporters (ABCG2) (Allikmets et al., 1998;Doyle et al., 1998;Miyake et al., 1999;Doyle and Ross, 2003). The BCRP gene is located at 4q22 and encodes a 72-kDa membrane protein composed of 655 amino acids (Allikmets et al., 1998;Doyle et al., 1998;Allen et al., 1999;Bailey-Dell et al., 2001). In contrast to many other ABC transporters, BCRP has only one ATP-binding region and one transmembrane domain. Therefore, BCRP is referred to as a half-transporter, and its homodimerization may be necessary to transport substrates .In normal human tissues, BCRP is highly expressed in the placenta, colon, small intestine, and liver (Maliepaard et al., 2001). On the basis of its tissue distribution and findings in knockout mice, BCRP is speculated to have a major influence on the pharmacokinetic and pharmacodynamic profiles of certain xenobiotics and endogenous substrates. For example, inhibition of mouse Bcrp 1 by GF120918, a dual inhibitor for BCRP and P-glycoprotein, has been demonstrated to increase the bioavailability of topotecan when GF120918 was administered orally to mdr1a/1b(Ϫ/Ϫ) mice (Jonker et al., 2000). In a clinical study, coadministration of GF120918 was also associated with a marked increase in the bioavailability of and systemic exposure to topotecan (Kruijtzer et al., 2002).Recent clinical studies indicate that the large interindividual variability in drug response occurs as a result of molecular alterations to various proteins such as drug-metabolizing enzymes, drug targets and receptors, and drug transporters. Most studies on molecular alterations have focused on the impact of single-nucleotide polymorphisms (SNPs) on the expression and function of these proteins (Evans and Relling, 1999;Evans and Johnson, 2001). Several groups have reported naturally occurring SNPs in the BCRP gene. G34A and C421A occur at relative...
Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillinresistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h) ؍ 2.85 ؋ (creatinine clearance/60.9) 0.618 ؋ 0.472 CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, <30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.
Organic cation transporters (OCTs) are responsible for the hepatic and renal transport of metformin. In this study we analyzed variants of OCT1 and OCT2 genes in 33 patients (24 responders and nine non-responders) based on the hypothesis that polymorphisms in both genes contribute to large interpatient variability in the clinical efficacy of metformin. The sequences of the 5¢-flanking and coding regions of the two genes of interest were screened by singlestrand conformation polymorphism (SSCP) analysis. To compare the causative factors between responders and non-responders, we performed stepwise discriminant functional analysis. Age, body mass index (BMI) and treatment with lipid-lowering agents were demonstrated as positive predictors, and two mutations in the OCT1 gene, -43T > G in intron 1 and 408Met > Val (1222A > G) in exon 7, were negative and positive predictors, respectively, for the efficacy of metformin; the predictive accuracy was 55.5% (P < 0.05). Subsequent study indicated that OCT1 mRNA levels tended to be lower in human livers with the 408Met (1222A) variant, though the differences did not reach the level of significance. In this study it is suggested that OCT1 and OCT2 gene polymorphisms have little contribution to the clinical efficacy of metformin.
There has been an increasing appreciation of the role of drug transporters in the pharmacokinetic and pharmacodynamic profiles of certain drugs. Among various drug transporters, P-glycoprotein, the MDR1 gene product, is one of the best studied and characterised. P-glycoprotein is expressed in normal human tissues such as liver, kidney, intestine and the endothelial cells of the blood-brain barrier. Apical (or luminal) expression of P-glycoprotein in these tissues results in reduced drug absorption from the gastrointestinal tract, enhanced drug elimination into bile and urine, and impeded entry of certain drugs into the central nervous system. The clinical relevance of P-glycoprotein depends on the localisation in human tissues (i.e. vectorial or directional movement), the therapeutic index of the substrate drug and the inherent inter- and intra-individual variability. With regard to the variability, polymorphisms of the MDR1 gene have recently been reported to be associated with alterations in disposition kinetics and interaction profiles of clinically useful drugs, including digoxin, fexofenadine, ciclosporin and talinolol. In addition, polymorphism may play a role in patients who do not respond to drug treatment. Moreover, P-glycoprotein is an important prognostic factor in malignant diseases, such as tumours of the gastrointestinal tract.A growing number of preclinical and clinical studies have demonstrated that polymorphism of the MDR1 gene may be a factor in the overall outcome of pharmacotherapy for numerous diseases. We believe that further understanding the physiology and biochemistry of P-glycoprotein with respect to its genetic variations will be important to establish individualised pharmacotherapy with various clinically used drugs.
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