First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.
[1] This paper investigates two complementary pieces of data on households' demand for improved water services, coping costs and willingness to pay (WTP), from a survey of 1500 randomly sampled households in Kathmandu, Nepal. We evaluate how coping costs and WTP vary across types of water users and income. We find that households in Kathmandu Valley engage in five main types of coping behaviors: collecting, pumping, treating, storing, and purchasing. These activities impose coping costs on an average household of as much as 3 U.S. dollars per month or about 1% of current incomes, representing hidden but real costs of poor infrastructure service. We find that these coping costs are almost twice as much as the current monthly bills paid to the water utility but are significantly lower than estimates of WTP for improved services. We find that coping costs are statistically correlated with WTP and several household characteristics.
Significance
The outer membrane (OM) of Gram-negative bacteria is composed of lipopolysaccharide (LPS) and glycerophospholipids (GPLs). Environmental regulation of LPS promotes bacterial resistance to host cationic antimicrobial peptides by altering surface charge and hydrophobicity. This work demonstrates that pathogenic
Salmonella
coordinately regulate GPL and LPS through the PhoPQ regulatory proteins and the OM palmitoyltransferase enzyme PagP. The broad conservation of PhoPQ and PagP in bacteria suggests that environmental regulation of OM GPL may be a conserved stress-response strategy for antimicrobial resistance. Improved understanding of OM GPL synthesis, transport, and modification could lead to new therapies that target the bacterial OM barrier.
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