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Predicting human pharmacokinetics (PK) during the drug discovery phase is valuable to assess doses required to reach therapeutic exposures. For orally administered compounds, however, this can be especially difficult, since the absorption process is complex. Vismodegib is a compound with unique nonlinear oral PK characteristics in humans. Oral physiologically based pharmacokinetic (PBPK) models were built using preclinical in vitro and in vivo data and successfully predicted the oral PK profiles in rats, dogs, and monkeys. Simulated drug exposures (area under the concentration-time curve from time 0 to infinity and C

Objectives The share of adults cohabiting at later ages has risen in the past few decades, though little is known about income pooling among midlife cohabitors. Cohabitation could be an attractive option because partners may be able to preserve their economic autonomy and maintain assets for the next generation. Conversely, cohabitation may operate as an alternative to marriage, allowing midlife adults to combine their resources to achieve economies of scale without the legal obligations of marriage. This study compared income pooling among middle-aged remarried and cohabiting adults in the United States. Methods Data were from the nationally representative 2013 Families and Relationships Survey. The analytic sample included adults aged 50–65 who were cohabiting or remarried (N = 888). Logistic regression models were used to predict the likelihood of income pooling among cohabiting and remarried midlife adults, net of relationship, demographic, and economic characteristics. Results Aligning with the hypothesis that cohabitation and remarriage are distinct in middle age, the odds of income pooling were lower for cohabitors than remarrieds. However, the gap between cohabitors and remarrieds narrowed by later ages. Discussion This study provides insight into the economic organization of midlife cohabiting relationships, which may have implications for individual well-being and relationship decision-making among middle-aged couples.

Marital quality has been declining among recent cohorts, but whether this pattern characterizes middle-aged and older married adults is largely unknown. The doubling of the divorce rate among persons over the age of 50 years foretells poorer quality marriages for today’s midlife adults than a generation ago. Combining data on married individuals aged 50–65 years from the 1987-88 National Survey of Families and Households (NSFH) and the 2013 Families and Relationships Study, we conduct a cohort comparison of five dimensions of midlife marital quality. Today’s older adults report more marital disagreement and instability as well as less fairness and interaction with their spouses than their counterparts did a generation ago. The two cohorts report comparable levels of marital happiness. Consistent with the upward trend in divorce during the second half of life, the quality of midlife marriages appears to have declined over the past quarter century.

The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel pain target due to its striking human genetics. However, clinically available drugs (e.g. lidocaine, carbamazepine, etc.) are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9, and the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. Moreover, understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidateGDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor series. To advance inhibitor design targeting the NaV1.7 channel, we established an iterative system to routinely obtain high-resolution ligand-bound NaV1.7 structures using cryogenic electron microscopy (cryo-EM). We report thatGDC-0310engages the NaV1.7 voltage-sensing domain 4 (VSD4) through an unexpected binding mode orthogonal to the arylsulfonamide class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, this study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. It also underscores an important role of the membrane bilayer in the discovery of selective NaV channel modulators.

The improvement in the ability of the pharmaceutical industry to predict human pharmacokinetic behavior are attributable to major technological shifts from 1990 to the present day. The opportunity for the application of AI/ML based approaches in the pharmaceutical industry is driven by the abundance of data sets that exist within individual pharmaceutical and biotech companies and the availability, within these environments, of abundant computing power. This chapter seeks to describe opportunities for artificial intelligence to contribute to the assessment and evaluation of the dug metabolism and pharmacokinetic (DMPK) properties of novel compounds across the drug discovery and development continuum. Many initiatives are already underway with respect to the application of AI/ML in predicting pharmacokinetic profiles so the question is not whether AI will influence pharmacokinetic prediction but rather how to best utilize and incorporate this and how to evaluate the value added from these applications. Since our understanding of the underlying biology of the in vitro and in vivo systems with respect to ADME, one of the key challenges to AI-based methods will be the ability to adapt to data sets that change in quality over time.

Objectives Loneliness in later life is associated with poorer health and higher risk of mortality. Our study assesses whether gray divorced adults report higher levels of loneliness than the widowed and whether social support or repartnership offset loneliness. Method Using data from the 2010 and 2012 Health and Retirement Study, we estimated ordinary least squares regression models for women (n = 2,362) and men (n = 1,127) to examine differences in loneliness by dissolution pathway (i.e., divorce versus widowhood), accounting for social support and repartnership. Results Divorced men were lonelier than their widowed counterparts. Although social support reduced loneliness among men, the difference between the divorced and widowed persisted. Repartnership assuaged men’s loneliness and reduced the variation between divorced and widowed men. Among women, the results did not reveal differences in loneliness for the divorced and widowed although social support and repartnership linked to less loneliness. Discussion Later-life marital dissolutions increasingly occur through divorce rather than spousal death. Some older adults go on to form new partnerships. Our findings demonstrate the importance of gerontological research widening the lens beyond widowhood to consider the ramifications of later-life divorce and repartnership for well-being.

Objectives Later life marital patterns have undergone shifts over the past few decades, including a rapid growth of cohabiting unions. Despite the increase in older adult cohabitation, research on this population has been slow to keep up. Intimate relationships are linked to well-being and relationship quality is especially important because high-quality relationships offer a number of benefits for well-being, whereas poor-quality relationships often are detrimental. This study compares cohabiting and remarried individuals on two measures of relationship quality. Method Using data from the 2010 and 2012 Health and Retirement Study, I investigate the positive and negative relationship quality of cohabitors relative to their remarried counterparts and whether the association of union type and relationship quality varies by race. Results Across both positive and negative relationship quality, I found few differences between cohabiting and remarried individuals. Black cohabitors report higher positive relationship quality than remarrieds, whereas White cohabitors and remarrieds do not differ. Discussion These findings suggest that cohabiting unions and remarriages are comparable among White older adults, but that Black cohabitors may gain more in terms of positive relationship quality than their remarried counterparts.

The doubling of the divorce rate among individuals over age 50 during the past 20 years underscores the urgency of studying the consequences of gray divorce and subsequent repartnering for adult well-being. We filled this gap by using the 1998-to-2014 Health and Retirement Study to evaluate how the levels of depressive symptoms changed following gray divorce versus widowhood. Individuals who divorced or became widowed already had experienced higher levels of depressive symptoms before dissolution relative to those who remained married. Compared with those who became widowed, those who transitioned to divorce experienced a lower elevation and a shorter time to recovery in depressive symptoms. When repartnering, both groups experienced similar magnitudes of initial reduction and subsequent rates of increase. Both the negative consequences of marital dissolution and the beneficial effects of repartnership for mental health persisted for several years, although ultimately they reverted to their predissolution levels of depressive symptoms.

The authors used data from the 1994, 2002, and 2012 General Social Survey ( N = 1,450) to examine whether support for divorce has increased among adults aged 50 years and older. Consistent with the rise in the gray divorce rate, today’s older adults were more accepting of divorce than their predecessors were two decades ago. Attitudinal change was modest between 1994 and 2002, but accelerated after 2002. The acceleration was primarily due to period rather than cohort change, signaling the role of broader shifts in the meaning of marriage as it has become deinstitutionalized. Older birth cohorts and individuals who were either divorced or remarried were especially likely to hold supportive attitudes toward divorce.

The doubling of the gray divorce rate (i.e., divorce at age 50 or older) over the past few decades portends growth in later-life repartnering, yet little is known about the mechanisms undergirding decisions to repartner after gray divorce. Using data from the 1998–2014 Health and Retirement Study, we examined women’s and men’s likelihoods of forming a remarriage or cohabiting union following gray divorce by estimating competing risk multinomial logistic regression models using discrete-time event history data. About 22 % of women and 37 % of men repartnered within 10 years after gray divorce. Repartnering more often occurred through cohabitation than remarriage, particularly for men. Resources such as economic factors, health, and social ties were linked to repartnering, but constraints captured by the contours of the marital biography were also salient, underscoring the distinctive features of union formation in later life.

Today's older adults are increasingly unmarried. Some are in cohabiting unions, others are dating, and many remain unpartnered. Unmarried older adults are at risk of poorer well-being than the married, but it is unclear whether older cohabitors fare worse than or similar to their married counterparts. Nor have well-being differences among cohabitors, daters, and unpartnered persons been considered. Conceptualizing marital status as a continuum of social attachment, data from Waves I and II of the National Social Life, Health, and Aging Project are used to examine how older married, cohabiting, dating, and unpartnered individuals differ across multiple indicators of psychological well-being. Among men, cohabitors appear to fare similarly to the married, and better than daters and the unpartnered. In contrast, there are few differences in psychological well-being by partnership status for women.

Older adults are at the forefront of family change as a declining share experiences lifelong marriage and rates of cohabitation and divorce in later life continue to rise. The goal of this article is to review recent scholarship on marriage, cohabitation, and divorce among older adults and identify directions for future research. The varied family experiences characterizing the later life course demonstrate the importance of moving beyond marital status to capture additional dimensions of the marital biography, including transitions, timing, duration, and sequencing. Cohabitation operates as an alternative to marriage for older adults and is increasingly replacing remarriage following divorce or widowhood. The gray divorce rate has doubled in recent decades as older adults abandon marriage in favor of unmarried partnerships or singlehood. The retreat from marriage among older adults raises important questions about the ramifications of family change for health and well-being as well as access to caregivers given that spouses historically have been the primary source of care.

Objectives Increasingly, older adults are experiencing divorce, yet little is known about the risk factors associated with divorce after age 50 (termed "gray divorce"). Guided by a life course perspective, our study examined whether key later life turning points are related to gray divorce. Method We used data from the 1998-2012 Health and Retirement Study to conduct a prospective, couple-level discrete-time event history analysis of the antecedents of gray divorce. Our models incorporated key turning points (empty nest, retirement, and poor health) as well as demographic characteristics and economic resources. Results Contrary to our expectations, the onset of an empty nest, the wife's or husband's retirement, and the wife's or husband's chronic conditions were unrelated to the likelihood of gray divorce. Rather, factors traditionally associated with divorce among younger adults were also salient for older adults. Marital duration, marital quality, home ownership, and wealth were negatively related to the risk of gray divorce. Discussion Gray divorce is especially likely to occur among couples who are socially and economically disadvantaged, raising new questions about the consequences of gray divorce for individual health and well-being.

The purpose of this test was to evaluate the effects of calcium magnesium acetate (CMA) and sodium chloride (NaCl)—two common substances used to de-ice roadways—on the corrosion and fatigue behavior of annealed AISI 4140 steel. When CMA-corroded, NaCl-corroded, and as-machined samples were tested using R = 0.1, and f = 20 Hz, it was found that, within the scope of this study, samples corroded in both 3.5% CMA solution and 3.5% NaCl solution exhibited a lower fatigue strength than samples tested in the as-machined, uncorroded condition. For the short lives tested in this study, the difference in the effects of CMA and NaCl is minimal. However, at longer lives it is suspected, based on the trends, that the CMA solution would be less detrimental to the fatigue life.

GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) that specifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC50) of ∼2 nM, with a selectivity index (50% cytotoxic concentration/EC50) of ∼2,000. The antiviral potency of GS-9160 decreased by 6- to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.

A series of C3 halobenzyl-substituted tricyclic HIV integrase inhibitors was prepared. Improvement in cell-based inhibitor potency was observed in comparison to previously disclosed tricyclic pyrroloquinolines carrying the ‘halobenzyl tail’ at the lactam nitrogen. Animal PK for several of the C3-substituted inhibitors was examined, with a dihaloaryl analog achieving good balance in protein-shifted EC50 and t1/2 in animal PK studies.

A series of C5-aza tricyclic HIV integrase inhibitors was prepared. A highly potent and orally bioavailable compound (compound 9) was identified and selected for development.

We collected modern foraminiferal samples to characterize the foraminiferal environments and investigate the role that temporal and spatial variability may play in controlling the nature and significance of foraminiferal assemblages of the mangroves of Kaledupa, Wakatobi Marine National Park, Southeast Sulawesi, Indonesia. The study of foraminiferal live and dead assemblages indicates that dead assemblages are least prone to vary in time and space, and furthermore, they accurately represent the subsurface assemblages that are the focus of paleoenvironmental reconstructions. Further analyses of the dead assemblages indicate a vertical zonation of foraminifera within the intertidal zone. Zone D-Ia is dominated by agglutinated foraminifera Arenoparrella mexicana, Miliammina fusca , M. obliqua and Trochammina inflata . Zone D-Ib has mixed agglutinated/calcareous assemblages with species such as T. inflata and Ammonia tepida. Zone D-II is dominated by numerous calcareous species including A. tepida , Discorbinella bertheloti, Elphidium advenum and Quinqueloculina spp. Zone D-Ia is found to be the most accurate sea-level indicator and its assemblages are omnipresent world-wide. Zones D-Ib and D-II are subject to both spatial and temporal variations which must be included in any sea-level reconstructions.

Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.

Contemporary foraminiferal samples and associated environmental information were collected from Cocoa Creek, a mesotidal fringing mangrove environment on the Great Barrier Reef (GBR) coastline, Australia, to elucidate the relationship of the foraminiferal assemblages with elevation and environment. There is a strong and highly significant relationship between elevation and the foraminiferal assemblages, supporting the intertidal vertical zonation concept, which suggests that the distribution of foraminifera in the intertidal zone is usually a direct function of elevation, with the most important controlling factors being the duration and frequency of subaerial exposure. Multivariate analyses separate the intertidal foraminiferal assemblages into three elevational zones, with Zone I the highest and Zone III the lowest: Zones I and II are dominated by agglutinated species Trochammina inflata and Miliammina fusca , respectively; and Zone III is dominated by calcareous species, notably Ammonia tepida and Elphidium discoidale multiloculum . These assemblage zones are similar to those found in both tropical and temperate intertidal environments. A predictive transfer function has been developed to allow reconstruction of former sea levels for tropical environments, based upon the relationship between foraminiferal assemblage and elevation. Results suggest that a precision of ±0.07 m should be attainable, superior to most similar studies from temperate, mid latitude environments. Our work has produced the first foraminifera-based transfer function for environmental interpretations for tropical Australia, and allows the potential development of a new generation of high-resolution sea-level reconstructions for the post-glacial sequences of the GBR shelf.

A series of P1/P1' substituted cyclic urea analogues were prepared in an attempt to increase the intra-cellular antiviral potency of the nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851. The effect of alkyl substitution of the P1/P1' residues on cellular antiviral potency, protein binding, resistance profile and pharmacokinetics are described.

Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P 1 substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 ( 12 ) inhibits fXa with a K i value of 0.35 nM and is very selective for fXa over thrombin and trypsin.

DPC423 [1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide] is a synthetic, competitive, and selective inhibitor of coagulation factor Xa (fXa) (K(i): 0.15 nM in humans, 0.3 nM in rabbit). The objective of this study was to compare effects of DPC423, enoxaparin (low-molecular-weight heparin), and argatroban (thrombin inhibitor) on arterial thrombosis and hemostasis in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding, respectively. Compounds were infused i.v. continuously from 60 min before artery injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. Antithrombotic ED(50) values were 0.4 mg/kg/h for enoxaparin (n = 6), 0.13 mg/kg/h for argatroban (n = 6), and 0.6 mg/kg/h for DPC423 (n = 12). DPC423 at the maximum antithrombotic dose increased activated partial thromboplastin time and prothrombin time (n = 6) by 1.8 +/- 0.07- and 1.8 +/- 0.13-fold, respectively, without changes in thrombin time and ex vivo thrombin activity. The antithrombotic effect of DPC423 was significantly correlated with its ex vivo anti-fXa activity (r = 0.86). DPC423 at 1, 3, and 10 mg/kg p.o. increased carotid blood flow (percent control) at 45 min to 10 +/- 4, 24 +/- 6, and 74 +/- 7, respectively (n = 6/group). Cuticle bleeding times (percent change over control) determined at the maximum antithrombotic dose were 88 +/- 12 for argatroban, 69 +/- 13 for heparin, 4 +/- 3 for enoxaparin, 5 +/- 4 for DPC423, and -3 +/- 2 for the vehicle (n = 5-6/group), suggesting dissociation of antithrombotic and bleeding time effects for DPC423 and enoxaparin. The combination of aspirin and DPC423 at ineffective antithrombotic doses produced significant antithrombotic effect. Therefore, these results suggest that DPC423 is a clinically useful oral anticoagulant for the prevention of arterial thrombosis.

Objectives. Our study trac ks cohort change in the attitudes of adults aged 50 and older toward cohabitation from 1994 to 2012. Method. W e used data from the 1994, 2002, and 2012 waves of the General Social Survey to examine the roles of cohort replacement and intracohort change in the trend toward favorable cohabitation attitudes and to examine sociodemographic variation in patterns of support for cohabitation. Results. Suppor t for cohabitation accelerated over time with nearly half (46%) of older adults reporting favorable attitudes toward cohabitation in 2012 versus just 20% in 1994. This shift in older adults’ attitudes largely reflected cohort replacement rather than intracohort change. Some of the factors associated with later life cohabitation experience were linked to supportive attitudes. Discussion. Cohor t succession is fueling the growing acceptance of cohabitation among older adults and coincides with the rapid growth in later life cohabitation that has occurred in recent decades.

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.

This paper presents the results of an investigation into Holocene relative sea-level (RSL) change, isostatic rebound and ice sheet dynamics in Disko Bugt, West Greenland. Data collected from nine isolation basins on Arveprinsen Ejland, east Disko Bugt, show that mean sea level fell continuously from ca. 70 m at 9.9 ka cal. yr BP (8.9 ka 14C yr BP) to reach a minimum of ca. −5 m at 2.8 ka cal. yr BP (2.5 ka 14C yr BP), before rising to the present day. A west–east gradient in isostatic uplift across Disko Bugt is confirmed, with reduced rebound observed in east Disko Bugt. However, RSL differences (up to 20 m at 7.8 ka to 6.8 ka cal. yr BP (7 ka to 6 ka 14C yr BP)) also exist within east Disko Bugt, suggesting a significant north–south component to the area’s isostatic history. The observed magnitude and timing of late Holocene RSL rise is not compatible with regional forebulge collapse. Instead, RSL rise began first in the eastern part of the bay, as might be expected under a scenario of crustal subsidence caused by neoglacial ice sheet readvance. The results of this study demonstrate the potential of isolation basin data for local and regional RSL studies in Greenland, and the importance of avoiding data compilations from areas where the isobase orientation is uncertain. Copyright © 1999 John Wiley & Sons, Ltd.

Objectives Our study compares two types of later life marital dissolution that occur after age 50-divorce and widowhood-and their associations with repartnership status (i.e., remarried, cohabiting, or unpartnered). Method We used data from the Health and Retirement Study to provide a portrait of later life divorce and widowhood for women and men. Next, we tested whether marital dissolution type is related to women's and men's repartnered status, distinguishing among remarrieds, cohabitors, and unpartnereds, net of key sociodemographic indicators. Results Divorcees are more often repartnered through either remarriage or cohabitation than are widoweds. This gap persists among women net of an array of sociodemographic factors. For men, the differential is reduced to nonsignificance with the inclusion of these factors. Discussion Later life marital dissolution increasingly occurs through divorce rather than widowhood, and divorce is more often followed by repartnership. The results from this study suggest that gerontological research should not solely focus on widowhood but also should pay attention to divorce and repartnering during later life.

Flurbiprofen is a chiral 2-arylpropionate used clinically as a racemate. Previously a significant pharmacokinetic interaction between the enantiomers of flurbiprofen has been reported in both rats and humans. The possible mechanism for this interaction was believed to involve competitive protein binding between the enantiomers. In addition, the saturable binding of flurbiprofen enantiomers in vitro in human plasma has been demonstrated. In this study different doses of racemic flurbiprofen were administered to rats to create differing extents of competition for protein binding sites between the enantiomers. There was a statistically significant dose-dependent increase in total body clearance and volume of distribution of both the R and S enantiomers. However, there was no change in either the S/R AUC ratio or the elimination rate constants for (R)- or (S)-flurbiprofen with increasing dose. These results are consistent with the hypothesis that the increasing amount of (R)- and (S)-flurbiprofen in the body causes displacement of flurbiprofen enantiomers from their protein binding sites, resulting in their increased total body clearance and volume of distribution. Further, the data suggest that previously reported extents of R to S enantiomeric inversion for other 2-arylpropionates may not be accurate if the enantiomers exhibit nonlinear kinetics or there is a significant kinetic interaction between the enantiomers.

Although the implications of stereochemistry for pharmacokinetics are relatively well appreciated only recently has its influence on pharmacodynamics begun to be examined. The implications of different pharmacological interactions between enantiomers with similar and different kinetic properties are examined through the use of simulation of the pharmacological effect vs. time profile. The influences of assuming that the pharmacological effect is solely the result of the more active enantiomer are also discussed. The simulations demonstrate that the less pharmacologically active enantiomer may have a significant influence on the observed effect vs. time profile and that the assumption that all of the observed pharmacological activity arises from the more active enantiomer may lead to highly inaccurate prediction of the pharmacodynamic parameters. Finally, these observations suggest that the pharmacodynamic profiles of a drug administered as a racemate or as a “pure” formulation of the more active enantiomer may be significantly different. © 1994 Wiley-Liss, Inc.

Excretion of orally administrated 51Cr-EDTA as a marker of small intestinal permeability (a proposed prerequisite for human enteropathy) is increased by corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). We have investigated the suitability of the rat as an animal model of small intestinal permeability using orally administered 51Cr-EDTA. We dosed Sprague-Dawley rats with NSAIDs and corticosterone followed by 51Cr-EDTA under conditions reported for humans and measured urinary excretion of the marker. In control rats, the urinary excretion of 51Cr-EDTA exhibited a skewed-to-the-left frequency distribution curve with a median of 2.13% of the dose. No sex-related differences were noticed in the baseline permeability. In male rats, single therapeutically equivalent doses of indomethacin, flurbiprofen, ibuprofen, naproxen, diclofenac, sulindac, nambumetone, and corticosterone, increased the intestinal permeability by different extents with indomethacin eliciting the maximum effect, and the last four drugs showing minimal potencies. Therapeutically relevant doses of aspirin did not have any significant effect. The increase in permeability was dependent upon the NSAIDs dose. Administration of glucose/citrate, misoprostol and sulfasalazine significantly reduced the effect of indomethacin. Misoprostol antagonized the effect of naproxen but H2-antagonists and sucralfate did not. All the above observations made in the rat were similar to those previously reported for humans. Thus the rat is a suitable model for studies of small intestinal permeability.

A potential problem with chiral derivatization is the possibility of stereochemical conversion during the derivatization reaction. This possibility has been examined using the non-steroidal anti-inflammatory drugs ibuprofen, ketoprofen, etodolac and flurbiprofen. To avoid possible interference from stereochemical impurities, male Sprague-Dawley rats were dosed intraperitoneally with the S enantiomer (100 mg/kg) of each drug and the R enantiomer of etodolac. Blood samples were taken 4 h afterwards. The plasma samples were analyzed using published stereospecific methods involving chiral derivatization with ethyl chloroformate followed by either R-(+)-alpha-phenylethylamine or L-leucinamide. For all the drugs examined, the percentage of formation of the antipode was between 1.0 and 5.8%. In vitro studies of the R and S enantiomers demonstrate that the apparent extent of conversion is inversely related to the concentration of ethyl chloroformate present during the derivatization reaction for ibuprofen, ketoprofen and flurbiprofen but not for etodolac. However, both the R and S enantiomers appear to be inverted to the same extent in the presence of ethyl chloroformate. These results suggest that the degree of stereochemical conversion induced by these assay procedures is small and would not contribute significantly to analytical error in the absence of a large difference in concentrations of the enantiomers.

(1993). Bioequivalence: Stereochemical Considerations. Clinical Research and Regulatory Affairs: Vol. 10, No. 1, pp. 1-11.

3,4,5-Trisubstituted isoxazolines (2) and isoxazoles (3) were prepared and evaluated for their in vitro and in vivo antithrombotic efficacy. They were compared to 3,5,5-trisubstituted isoxazolines (1) for Factor Xa selectivity and potency. They were also compared in an arterio-venous (A-V) shunt model of thrombosis.

SAR studies on the para-fluorobenzyl moiety of tricyclic HIV integrase inhibitors are discussed and lead compounds with potency and PK properties comparable to raltegravir were identified.

The chimpanzee (CHP) was evaluated as a pharmacokinetic model for humans (HUMs) using propranolol, verapamil, theophylline, and 12 proprietary compounds. Species differences were observed in the systemic clearance of theophylline (approximately 5-fold higher in CHPs), a low clearance compound, and the bioavailability of propranolol and verapamil (lower in CHPs), both high clearance compounds. The systemic clearance of propranolol (approximately 1.53 l/h/kg) suggested that the hepatic blood flow in CHPs is comparable to that in humans. No substantial differences were observed in the in vitro protein binding. A preliminary attempt was made to characterize cytochrome P450 (P450) activities in CHP and HUM liver microsomes. Testosterone 6beta-hydroxylation and tolbutamide methylhydroxylation activities were comparable in CHP and HUM liver microsomes. In contrast, dextromethorphan O-demethylation and phenacetin O-deethylation activities were approximately 10-fold higher (per mg protein) in CHP liver microsomes. Intrinsic clearance estimates in CHP liver microsomes were higher for propranolol (approximately 10-fold) and theophylline (approximately 5-fold) and similar for verapamil. Of the 12 proprietary compounds, 3 had oral clearances that differed in the two species by more than 3-fold, an acceptable range for biological variability. Most of the observed differences are consistent with species differences in P450 enzyme activity. Oral clearances of proprietary compounds in HUMs were significantly correlated to those from CHPs (r = 0.68; p = 0.015), but not to estimates from rat, dog, and monkey. In summary, the chimpanzee serves as a valuable surrogate model for human pharmacokinetics, especially when species differences in P450 enzyme activity are considered.