Publications

A Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters in determining drug bioavailability and disposition. BDDCS may be useful in predicting: routes of drug elimination; efflux and absorptive transporters effects on oral absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g. low drug bioavailability and drug-drug interactions); and transporter effects on post-absorptive systemic drug levels following oral and i.v. dosing. For highly soluble, highly permeable Class 1 compounds, metabolism is the major route of elimination and transporter effects on drug bioavailability and hepatic disposition are negligible. In contrast for the poorly permeable Class 3 and 4 compounds, metabolism only plays a minor role in drug elimination. Uptake transporters are major determinants of drug bioavailability for these poorly permeable drugs and both uptake and efflux transporters could be important for drug elimination. Highly permeable, poorly soluble, extensively metabolized Class 2 compounds present the most complicated relationship in defining the impact of transporters due to a marked transporter-enzyme interplay. Uptake transporters are unimportant for Class 2 drug bioavailability, (ensure space after,) but can play a major role in hepatic and renal elimination. Efflux transporters have major effects on drug bioavailability, absorption, metabolism and elimination of Class 2 drugs. It is difficult to accurately characterize drugs in terms of the high permeability criteria, i.e. > or =90% absorbed. We suggest that extensive metabolism may substitute for the high permeability characteristic, and that BDDCS using elimination criteria may provide predictability in characterizing drug disposition profiles for all classes of compounds.

BACKGROUND

Minority women are more likely than white women to choose tubal sterilization as a contraceptive method. Disparities in rates of unintended pregnancy may help explain observed racial/ethnic differences in sterilization, but this association has not been investigated.

OBJECTIVE

To examine the associations among race/ethnicity, unintended pregnancy, and tubal sterilization.

DESIGN AND PARTICIPANTS

Cross-sectional analysis of data from a nationally representative sample of women aged 15-44 years [65.7% white, 14.8% Hispanic, and 13.9% African American (AA)] who participated in the 2002 National Survey of Family Growth.

MAIN MEASURES

Race/ethnicity, history of unintended pregnancy, and tubal sterilization. A logistic regression model was used to estimate the effect of race/ethnicity on unintended pregnancy while adjusting for socio-demographic variables. A series of logistic regression models was then used to examine the role of unintended pregnancy as a confounder for the relationship between race/ethnicity and sterilization.

KEY RESULTS

Overall, 40% of white, 48% of Hispanic, and 59% of AA women reported a history of unintended pregnancy. After adjusting for socio-demographic variables, AA women were more likely (OR: 2.0; 95% CI: 1.6-2.4) and Hispanic women as likely (OR: 1.0; 95% CI: 0.80-1.2) as white women to report unintended pregnancy. Sterilization was reported by 29% of women who had ever had an unintended pregnancy compared to 7% of women who reported never having an unintended pregnancy. In unadjusted analysis, AA and Hispanic women had significantly higher odds of undergoing sterilization (OR: 1.5; 95% CI: 1.3-1.9 and OR: 1.4; 95% CI: 1.2-1.7, respectively). After adjusting for unintended pregnancy, this relationship was attenuated and no longer significant (OR: 1.2; 95% CI: 0.95-1.4 for AA women and OR: 1.3; 95% CI: 1.0-1.6 for Hispanic women).

CONCLUSION

Minority women, who more frequently experience unintended pregnancy, may choose tubal sterilization in response to prior experiences with an unintended pregnancy.

Von Recklinghausen neurofibromatosis is a common autosomal dominant genetic disorder characterized by benign and malignant tumors of neural crest origin. Significant progress in understanding the pathophysiology of this disease has occurred in recent years, largely aided by the development of relevant animal models. Von Recklinghausen neurofibromatosis is caused by mutations in the NF1 gene, which encodes neurofibromin, a large protein that modulates the activity of Ras. Here, we describe the identification and characterization of zebrafish nf1a and nf1b, orthologues of NF1, and show neural crest and cardiovascular defects resulting from morpholino knockdown, including vascular and cardiac valvular abnormalities. Development of a zebrafish model of von Recklinghausen neurofibromatosis will allow for structure-function analysis and genetic screens in this tractable vertebrate system.

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.