The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data.

We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.

Some comments on the thermodynamics of sonoluminescence--a personal view.

The path of the gas in a sonoluminescent bubble must enclose an area in a P-V plot if the gas itself emits photons. Thermodynamic analysis thus delineates the playing field that may enable us to distinguish liquid-phase emissions from gas-phase emissions. The apparent importance of the van der Waals a (which parameterizes mean-square induced dipole attractions) in light intensity supports collision-induced emission as a likely mechanism. The suggested emitting object, containing 10(10) molecules in picosecond-long van der Waals contact, is novel, being neither plasma, gas, liquid nor blackbody. The bubble pursues a unique thermodynamic path.

Diversity of eukaryotic microorganisms: computer-based resources, "The Handbook of Protoctista" and its "Glossary".

The kingdom Protoctista comprises some 30 phyla, including the eukaryotic anaerobes that permanently lack mitochondria, the Phylum Archaeprotista, with its three classes: (i) Archamoebae, e.g., Pelomyxa, Mastigina, (ii) Metamonada, e.g., Giardia, Pyrsonympha, and (iii) Parabasalia, e.g., Trichomonas, Calonympha, and the Phylum Microspora (Microsporidia), e.g., Vairimorpha. These and all algae, protozoa, labyrinthulids, "water molds" (oomycota, plasmodiophorans, hyphochytrids, chytrids, etc.) and other eukaryotes excluded from plants, animals and fungi are detailed in the Handbook of Protoctista. The Illustrated Glossary of Protoctista contains descriptions of the morphology and taxonomy of these microorganisms, including the many equivalent and homologous structures with different names. The Glossary has also been made into a Macintosh-compatible CD-ROM disk.

Sperm competition and the persistence of genes for male homosexuality.

Homosexuality is increasingly recognized as having a genetic component. Why then does it persist, when common sense suggests that it should result in fewer offspring? Monozygotic-twin studies permit a rough estimate of the importance of genetics (70%) in the development of male homosexuality, and the proportion of homosexuals remains constant: Fisher's Theorem then tells us there is an advantage to the heterozygote, which we find need be no greater than 2%. Behavior and sperm competition suggest what this advantage might be.

The use of metabolic inhibitors in the analysis of eukaryotic DNA repair.

By now, it is well established that DNA repair can be inhibited. It is not surprising that many inhibitors of replicative DNA synthesis also effect repair, since the two processes involve similar biochemical steps carried out by analogous if not identical enzymes. No specific inhibitors of repair are known, and care must be taken when interpreting results to be sure that observed effects of inhibitors unambiguously relate to repair. With this caveat, it remains true that inhibitors are valuable tools for the dissection of repair pathways in the classic biochemical fashion, looking for accumulation of intermediates at a point before the enzymic step that is blocked.

Serum cyclosporin levels, hepatic drug metabolism and renal tubulotoxicity.

The present study was designed to examine inter-relationships between serum cyclosporin (CsA) levels, hepatic drug metabolising enzyme activity and CsA induced nephrotoxicity. CsA (25 mg/kg p.o.) was administered daily to male Sprague-Dawley rats: groups of animals were killed on days 0, 4, 7, 10 and 14 and thereafter at weekly intervals over the 7-week course of the experiment. Nephrotoxicity was evaluated by measuring tubular enzymuria and by light microscopy and serum CsA levels (parent drug plus certain metabolites) were determined by radioimmunoassay. The hepatic microsomal mono-oxygenase enzyme system was monitored by measurement of cytochrome P-450, aminopyrine N-demethylase and NADPH-cytochrome c reductase. Nephrotoxicity appeared within 4 days of starting treatment and continued for 4 weeks. Between weeks 4 and 6 there was a period of complete remission followed by the return of renal damage. Aminopyrine N-demethylase activity fell during the first 4 weeks. During the period of remission, however, N-demethylase activity rose to a point significantly higher than pretreatment values and serum CsA levels fell to their lowest concentration. With relapse, hepatic N-demethylase activity again fell below normal and serum drug levels rose to their pre-remission values. From the third week onward, changes in NADPH-cytochrome c reductase activity paralleled those in N-demethylase activity. The hepatic microsomal concentration of cytochrome P-450 did not, however, change significantly during the 7-week period of CsA treatment. Our results suggest that the spontaneous remission of CsA-induced nephrotoxicity is due to a reduction in circulating drug levels caused by increased hepatic CsA metabolism.

Carbon-13 in tree rings indicates no record of sea-surface temperature.

When the correct values for the temperature coefficient of carbon dioxide solubility in seawater are used, theoretical calculations show that no measurable carbon-isotope redistribution occurs between sea and air for any plausible change in the sea-surface temperature. Although this fact invalidates one possible paleothermometer, it somewhat simplifies the interpretation of carbon-13 data in terrestrial biological samples.