Impact of drug transporter pharmacogenomics on pharmacokinetic and pharmacodynamic variability - considerations for drug development

INTRODUCTION: Drug transporter proteins are expressed on the cell membrane, regulating substrate exposure in systemic circulation and/or peripheral tissues. Genetic polymorphism of drug transporter genes encoding these proteins could alter the functional activity and/or protein expression, having effects on absorption, distribution, metabolism and excretion (ADME), efficacy and adverse effects. AREAS COVERED: The authors provide the reader with an overview of the pharmacogenetics (PGx) of 12 membrane transporters. The clinical literature is summarized as to the quantitative significance on pharmacokinetics (PK) and implications on pharmacodynamics (PD) and adverse effects, due to transporter influence on intracellular drug concentrations. EXPERT OPINION: Unlike polymorphisms for cytochrome P450s (CYPs) resulting in large magnitude of PK variation, genetic mutations for membrane transporters are typically less than threefold alteration in systemic PK for drugs with a few exceptions. However, substantially greater changes in intracellular drug levels may result. We are aware of 1880 exome variants in 12 of the best-studied transporters to date, and nearly 40% of these change the amino acid. However, the functional consequences of most of these variants remain to be determined, and have only been empirically evaluated for a handful. To the extent that genetic polymorphisms impact ADME, it is a variable that will contribute to ethnic differences due to substantial frequency differences for the known variants.     

Differential modulation of cytochrome P450 activity and the effect of 1-aminobenzotriazole on hepatic transport in sandwich-cultured human hepatocytes

Sandwich-cultured human hepatocytes (SCHH) have been widely used for in vitro assessments of biliary clearance. However, the modulation of metabolism enzymes has not been fully evaluated in this system. The present study was therefore undertaken to determine the activity of cytochrome P450 (P450) 1A2, 2C8, 2C9, 2C19, 2D6, and 3A and to evaluate the impact of 1-aminobenzotriazole (ABT) on hepatic uptake and biliary excretion in SCHH. The SCHH maintained integrity and viability as determined by lactate dehydrogenase release and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays conducted over the culture period. Although all assessed P450 activity decreased in day 2 SCHH, the extent of the decrease and the subsequent rebound in activity varied across the different isoforms. Day 5 CYP1A2 activity was approximately 2.5-fold higher than day 1 activity, whereas the CYP3A and CYP2C9 activities were 90 and 60% of the day 1 levels, respectively. In contrast, the initial CYP2C8, CYP2C19, and CYP2D6 activity losses did not rebound over the 5-day culture period. Furthermore, ABT was not found to have an effect, whether directly or indirectly as a P450 inactivator, with respect to the hepatic transport of rosuvastatin, atrovastatin, and midazolam in SCHH. Taken together, these results suggest that the SCHH model is a reliable tool to characterize hepatic uptake and biliary excretion. Due to the differential modulation of P450 activity, SCHH may not be considered a suitable tool for metabolic stability assessments with compounds predominantly cleared by certain P450 enzymes.     

Percutaneous image-guided aspiration versus catheter drainage of abdominal and pelvic collections

Purpose

Intra abdominal and pelvic fluid collection is a serious problem that requires drainage. The goal of our study was to report our experience and evaluate the feasibility, safety and outcome of percutaneous image-guided aspiration versus catheter drainage of abdominal and pelvic collections.

Patients and methods

This is a retrospective study of 84 patients (45 males and 39 females of mean age 45.1 + 16.9 years) who have intra abdominal or pelvic collections and have a good coagulation profile. Small (<5 cm) collections were treated by aspiration. Continuous catheter drainage was applied to failed aspirations or large collection.

Results

112 Drainage procedures were carried out in 84 patients guided by either ultrasound or CT. Aspirations of 31 collections were carried out in 22 patients, and 81 catheters (8–10 French) were inserted in 66 patients. Four patients had both aspirations and catheters. The collections were either sterile or pus. Median diameter of aspirated collections was 4.2 cm (3–5 cm) compared to 7.2 cm (6–12 cm) of those treated by catheters P < 0.05. Technical success was 100% in both aspiration and catheter insertion using the Seldinger technique but it was 87% with the trocar technique. Clinical success rate for aspiration was 94% (n = 29) but increased to 100% after catheter insertion and that of catheter was 95%. No major complications were encountered.

Conclusion

Image-guided drainage of abdominal and pelvic collections is safe and effective and can avoid surgery in selected patients. Aspiration should be tried before catheter insertion. Careful catheter selection for trochar technique is important.     

Generalized lichen nitidus

Lichen nitidus is a rare chronic condition of unknown etiology. Generalized lichen nitidus is even rarer. We report here a 5-year-old girl who had multiple, asymptomatic, discrete, 1 to 2 mm flesh-colored, shiny, flat, papules on her face, upper limbs, and thighs with relative sparing of the trunk. Resolution of these papular lesions was followed by hyperpigmented macules in those areas. Histopathologic examination of a papular lesion revealed a localized granulomatous lymphohistiocytic infiltrate in an expanded dermal papilla with thinning of overlying epidermis and downward extension of the rete ridges at the lateral margin of the infiltrate, producing a typical "claw clutching a ball" picture, confirming our clinical diagnosis of lichen nitidus. The pigmented macules showed melanin pigmentation on histology. There was no response to oral astemizole treatment for 3 months. However, the lichen nitidus lesions resolved spontaneously without any further treatment over the next year, leaving behind a prominent pigmentary disturbance.     

Morbidity with total laparoscopic and laparoscopically assisted vaginal hysterectomy

We evaluated the operative and postoperative morbidity among 103 women who underwent total laparoscopic hysterectomy and 107 others who underwent laparoscopically assisted vaginal hysterectomy. Blood loss was significantly greater in the assisted vaginal hysterectomy group (178.0 ± 12.1 ml) than in the total hysterectomy group (130.2 ± 10.7 ml) (p < 0.001). Despite higher uterine weight in the total hysterectomy group, the operative time of both techniques was similar. The complications of both hysterectomies were also comparable. The results from our study suggest that the complication rates of laparoscopically assisted vaginal hysterectomy and total hysterectomy are similar. However, laparoscopically assisted vaginal hysterectomy is associated with increased blood loss.