Persistence and origin of the lunar core dynamo.

The lifetime of the ancient lunar core dynamo has implications for its power source and the mechanism of field generation. Here, we report analyses of two 3.56-Gy-old mare basalts demonstrating that they were magnetized in a stable and surprisingly intense dynamo magnetic field of at least ~13 µT. These data extend the known lifetime of the lunar dynamo by ~160 My and indicate that the field was likely continuously active until well after the final large basin-forming impact. This likely excludes impact-driven changes in rotation rate as the source of the dynamo at this time in lunar history. Rather, our results require a persistent power source like precession of the lunar mantle or a compositional convection dynamo.

A long-lived lunar core dynamo.

Paleomagnetic measurements indicate that a core dynamo probably existed on the Moon 4.2 billion years ago. However, the subsequent history of the lunar core dynamo is unknown. Here we report paleomagnetic, petrologic, and (40)Ar/(39)Ar thermochronometry measurements on the 3.7-billion-year-old mare basalt sample 10020. This sample contains a high-coercivity magnetization acquired in a stable field of at least ~12 microteslas. These data extend the known lifetime of the lunar dynamo by 500 million years. Such a long-lived lunar dynamo probably required a power source other than thermochemical convection from secular cooling of the lunar interior. The inferred strong intensity of the lunar paleofield presents a challenge to current dynamo theory.

Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors.

BACKGROUND: Active renal secretion of tenofovir (TFV) across proximal tubules occurs via uptake by human organic anion transporters 1 and 3 (hOAT1 and hOAT3) coupled with efflux by multidrug resistance protein 4 (MRP4). Co-administration of some HIV protease inhibitors (PIs) with tenofovir disoproxil fumarate (TDF), an oral prodrug of TFV, has been shown to increase systemic levels of TFV, leading to a hypothesis that PIs may affect tubular secretion of TFV and potentially alter the renal safety of TDF. METHODS: The effect of PIs on the transport of TFV by hOAT1, hOAT3 and MRP4 was assessed using in vitro cell-based transport models. RESULTS: At concentrations equal to their therapeutic peak plasma levels (Cmax) all PIs showed <20% inhibition of TFV transport by hOAT1. hOAT3 was more sensitive to Pls with ritonavir (RTV) and lopinavir being the most potent inhibitors of TFV transport (62% and 37% inhibition, respectively, at their Cmax). In the absence of human serum, RTV at concentrations exceeding its therapeutic Cmax also exhibited a minor effect on the cellular efflux of TFV by MRP4 (<30% inhibition at 20 microM). However, no effects of PIs on hOAT1, hOAT3 or MRP4 were detected in the presence of human serum with the exception of RTV that inhibited hOAT3 by approximately 35% at its Cmax. In addition, PIs did not affect the cytotoxicity of TFV or TDF in MRP4- or MRP2-overexpressing cells. CONCLUSION: These data indicate a low potential of PIs to interfere with the active tubular secretion of TFV and to alter the clinical renal safety profile of TDF.

Mechanism of active renal tubular efflux of tenofovir.

Tenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake of TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about the efflux system responsible for transporting TFV into the lumen during active tubular secretion. Therefore, members of the ATP-binding cassette family of efflux pumps expressed at the apical side of proximal-tubule cells were studied for the ability to transport TFV. Studies in multiple independent in vitro systems show TFV not to be a substrate for P glycoprotein (Pgp) or multidrug resistance protein type 2 (MRP2). In contrast to Pgp and MRP2, TFV was observed to be a substrate for MRP4. TFV accumulated to fivefold lower levels in MRP4-overexpressing cells, and its accumulation could be increased by an MRP inhibitor. Furthermore, MRP4-overexpressing cells were found to be 2.0- to 2.5-fold less susceptible to cytotoxicity caused by TFV. ATP-dependent uptake of TFV was observed in membrane vesicles containing MRP4 but not in vesicles lacking the transporter. On the basis of these and previous results, the molecular transport pathway for the active tubular secretion of TFV through renal proximal-tubule cells involves uptake from the blood mediated by human organic anion transporters 1 and 3 and efflux into urine by MRP4. A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents.