@inbook{riviere_carver_1991, title={Isolated perfused skin flap and skin grafting techniques}, ISBN={0849388112}, booktitle={Dermal and ocular toxicology: fundamentals and methods}, publisher={Boca Raton: CRC Press}, author={Riviere, J. E. and Carver, M. P.}, year={1991}, pages={297–322} }
 @article{williams_carver_riviere_1990, title={A PHYSIOLOGICALLY RELEVANT PHARMACOKINETIC MODEL OF XENOBIOTIC PERCUTANEOUS-ABSORPTION UTILIZING THE ISOLATED PERFUSED PORCINE SKIN FLAP}, volume={79}, ISSN={["1520-6017"]}, DOI={10.1002/jps.2600790407}, abstractNote={A physiologic pharmacokinetic model describing percutaneous absorption of topically applied compounds in the isolated perfused porcine skin flap (IPPSF) is presented. As an extension of a previously reported hybrid physiologically relevant compartmental model of uptake of intra-arterially administered drug in the IPPSF, this percutaneous model should allow experimental results obtained from an in vitro preparation to serve as quantitative input to an in vivo pharmacokinetic system. Model parameters estimated from 8-10-h IPPSF experiments were able to predict 6-day in vivo radiolabel absorptions in pigs for topically applied benzoic acid, caffeine, malathion, parathion, DFP, testosterone, and progesterone. These results compare favorably with those obtained previously using a classical compartmental modeling approach.}, number={4}, journal={JOURNAL OF PHARMACEUTICAL SCIENCES}, author={WILLIAMS, PL and CARVER, MP and RIVIERE, JE}, year={1990}, month={Apr}, pages={305–311} }
 @article{carver_levi_riviere_1990, title={Parathion metabolism during percutaneous absorption in perfused porcine skin}, volume={38}, ISSN={0048-3575}, url={http://dx.doi.org/10.1016/0048-3575(90)90096-k}, DOI={10.1016/0048-3575(90)90096-K}, abstractNote={The metabolism and disposition of topical parathion was examined in the isolated perfused porcine skin flap (IPPSF), a novel organ perfusion method developed for in vitro studies of the pharmacology and toxicology of skin. Ethanol solutions of 14C-radiolabeled parathion (1.0 mg/ml, 0.05 mCi/ml) were applied to the surface at a dose of 40 μg/cm2 on skin flaps representing three treatment groups: control (N = 5), occluded (N = 4), and 1-aminobenzotriazole (ABT)-pretreated (N = 2). Radiolabel uptake in the perfusion medium from 0–8 hr postapplication indicated that total chemical flux and peak rates of absorption in occluded preparations were 59% and 47% lower than in the controls (P < 0.05), and were both > 75% lower in the ABT-pretreated IPPSF's. Thin-layer chromatographs of ethyl acetate extracts demonstrated that most of the absorbed radiolabel recovered in the perfusion medium of the controls was paraoxon (67.8 ± 2.3%, mean ± SE), with a lesser amount of p-nitrophenol (14.5 ± 5.2%) and unmetabolized parathion (16.9 ± 4.1%). Occlusion of the application site increased the fraction of p-nitrophenol in the perfusion medium (43.0 ± 7.8%, P < 0.05), at the apparent expense of paraoxon (39.6 ± 17.8%, P < 0.05), without altering the mean percentage of parent compound recovered (17.4 + 10.1%). Pretreatment of the IPPSF by addition of 50 μg ABT/g wet tissue weight into the perfusion medium blocked most of the paraoxon formation (6.6%), but not that of p-nitrophenol (11.9%), while allowing 78.5% of the parathion absorbed to penetrate intact. Total flux assessments for parathion plus its metabolites (total radiolabel absorption) in vitro varied in conjunction with its fraction metabolized within the skin. Net permeation of unchanged parathion was similar in the control (580 ng/cm2) and ABT-pretreated skin flaps (660 ng/cm2), suggesting that the diffusivity of parathion molecules through skin was not altered by this metabolic inhibitor. In contrast, occlusion reduced the net flux of intact parathion molecules to approximately 240 ng/cm2. These findings show that parathion undergoes significant biotransformation following topical application to porcine skin and that the resultant cutaneous metabolite profiles can be altered by both physical (occlusion) and chemical (ABT) means.}, number={3}, journal={Pesticide Biochemistry and Physiology}, publisher={Elsevier BV}, author={Carver, Michael P. and Levi, Patricia E. and Riviere, J.Edmond}, year={1990}, month={Nov}, pages={245–254} }
 @article{carver_riviere_1989, title={PERCUTANEOUS-ABSORPTION AND EXCRETION OF XENOBIOTICS AFTER TOPICAL AND INTRAVENOUS ADMINISTRATION TO PIGS}, volume={13}, ISSN={["0272-0590"]}, DOI={10.1016/0272-0590(89)90329-1}, abstractNote={Interspecies comparisons suggest that the weaning pig is a suitable surrogate for man in percutaneous absorption studies. Despite known anatomical and physiological similarities between porcine and human skin, very few investigations of percutaneous absorption phenomena have been conducted in pigs. This study examined radiolabel excretion patterns after intravenous (iv) and topical administration of six 14C-radiolabeled compounds in weanling Yorkshire sows. Radiolabel recovery from excrement collected over 6 days following iv doses in physiological saline (200 μg, 10 μCi) showed that malathion (M), parathion (P), caffeine (C), and benzoic acid (B) were primarily excreted into urine (>80%), while greater fractions of testosterone (T, 72%) and progesterone (R, 35%) were fecally eliminated. Percutaneous absorption was determined from total urine and fecal excretion of radiolabel after topical application, corrected for incomplete excretion following iv administration. Topical doses in ethanol (200 μg, 10 μCi) were applied at a surface concentration of 40 μg cm−2 and penetrated in the following rank order (percentage dose): B (25.7%) > R (16.2%) > C (11.8%) > T (8.8%) > P (6.7%) > M (5.2%). Fecal clearances of radiolabel, expressed as a percentage of total excretion, were greater after topical administration for four of the six compounds (B, C, P, and T, p < 0.05). Calculations based on urinary excretion alone underestimated percutaneous absorption determined from total excretion by 5–30%, although the difference between the two estimates was statistically significant only for C (p < 0.05). These results suggest that percutaneous absorption estimates based on urinary radiolabel excretion alone should be interpreted with caution whenever compounds with unknown penetration characteristics are used. Factors known to affect human skin absorption, such as applied dose, anatomical region, sex, age, various vehicles and solvents, and differences in cutaneous metabolism, should be more closely examined in all animal species used to model percutaneous absorption phenomena in man.}, number={4}, journal={FUNDAMENTAL AND APPLIED TOXICOLOGY}, author={CARVER, MP and RIVIERE, JE}, year={1989}, month={Nov}, pages={714–722} }
 @article{carver_williams_riviere_1989, title={THE ISOLATED PERFUSED PORCINE SKIN FLAP .3. PERCUTANEOUS-ABSORPTION PHARMACOKINETICS OF ORGANOPHOSPHATES, STEROIDS, BENZOIC-ACID, AND CAFFEINE}, volume={97}, ISSN={["0041-008X"]}, DOI={10.1016/0041-008X(89)90337-2}, abstractNote={The isolated perfused porcine skin flap (IPPSF) has been developed as an alternative in vitro tool for examining the pharmacokinetics and mechanisms of percutaneous absorption. In this study, dosing solutions of seven 14C-radiolabeled compounds representing three chemical classes—organic acid/base [benzoic acid (B), caffeine (C)], organophosphate (OP) pesticides (diisopropylfluorophosphidate, malathion, parathion), and steroid hormones (progesterone, testosterone)—were prepared in ethanol and applied topically at a surface concentration of 40 μg cm−2 to the IPPSF. A three-compartment pharmacokinetic model used to simulate mass transfer from the surface (C1), diffusion through epidermis and dermis (C2), and transfer into the capillary perfusate (C3), was developed based on flux through the IPPSF from 0 to 8 hr. This basic model accurately simulated measured IPPSF fluxes for five of seven compounds, including the OPs and steroids. The model was modified to simulate the shunting of drug to fast and slow release pathways, which occurred for B 3–4 hr postapplication, and to account for flow-dependent flux increases seen for C at 6 hr postapplication. The latter may be due to a direct pharmacologic effect, since C is a known vasodilator. Extrapolated (to 6 days) areas under the curve from the model simulations were compared with in vivo percutaneous absorption estimates, obtained from 6-day excretion studies in pigs. The in vivo-in vitro correlation, based on simple linear regression across compounds, was excellent (R2 = 0.88, R = 0.94, p < 0.002). These results suggest that xenobiotic penetration in the 8-hr IPPSF experiments is highly predictive of in vivo absorption totals (6-day studies). In addition, since pig and human skin are similar physiologically and pharmacologically, the IPPSF may eventually have applications in formulating human dermal risk assessment models.}, number={2}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={CARVER, MP and WILLIAMS, PL and RIVIERE, JE}, year={1989}, month={Feb}, pages={324–337} }
 @article{frazier_carver_dix_thompson_riviere_1986, title={Exaggerated response to gentamicin induced nephrotoxicity in Sprague Dawley rats: Identification of a highly sensitive outlier population}, volume={14}, DOI={10.1177/019262338601400209}, abstractNote={A number of factors have been shown to predispose patients treated with aminoglycosides to nephrotoxicity. In a previous study in our laboratory investigating the interaction of prior renal dysfunction with gentamicin toxicokinetics, 9.4% of rats in all treatment groups were relatively more sensitive to gentamicin-induced nephrotoxicity. To determine if these outliers had an underlying disease or physiological abnormality, serum was collected from 99 Sprague-Dawley rats prior to daily treatment with 75 mg/kg gentamicin for seven days. Urea nitrogen, creatinine, Na, K, Ca, Mg, P, total protein, albumin, aspartate transaminase, serum osmolality, total white and red blood cell count, hematocrit, hemoglobin, blood gases, and thyroxine were measured. Blood was collected one and four hours after the first dose of gentamicin for pharmacokinetic analysis. Elevations in post-treatment creatinine and nitrogen were significantly greater in the outliers (4.10 ± 0.24 mg/dl (n = 12) vs 1.92 ± 0.06 mg/dl (n = 87) and 146.4 ± 7.2 mg/dl (n = 12) vs 71.5 ± 2.0 mg/dl (n = 87); both p = 0.0001) and served as criteria for identifying this subgroup. Post-treatment creatinine and urea nitrogen were not normally distributed in the entire study population. However, when the population was divided into normal and sensitive subgroups, both subgroup values were normally distributed. The gentamicin pharmacokinetic profiles were similar in both groups. Postmortem histopathology showed significant increases in tubular casts and tubular necrosis (p = 0.01) in the sensitive rats, compared to the normally responding subgroup. Clinical tests on pre-treatment serum revealed significant differences only in serum osmolality (p = 0.04), total protein (p = 0.02), and oxygen tension (p = 0.01). The pre-treatment creatinine/urea nitrogen ratio was marginally decreased in the sensitive rats (p = 0.057).}, journal={Toxicologic Pathology}, author={Frazier, D. L. and Carver, M. P. and Dix, L. P. and Thompson, C. A. and Riviere, J. E.}, year={1986}, pages={204–209} }
 @article{riviere_dix_carver_frazier_1986, title={Identification of a subgroup of Sprague Dawley rats highly sensitive to drug induced renal toxicity}, volume={7}, journal={Fundamental and Applied Toxicology}, author={Riviere, J. E. and Dix, L. P. and Carver, M. P. and Frazier, D. L.}, year={1986}, pages={126–131} }
 @article{carver_shymodjeska_brown_rogers_riviere_1985, title={DOSE-RESPONSE STUDIES OF GENTAMICIN-NEPHROTOXICITY IN RATS WITH EXPERIMENTAL RENAL DYSFUNCTION .1. SUBTOTAL SURGICAL NEPHRECTOMY}, volume={80}, ISSN={["1096-0333"]}, DOI={10.1016/0041-008X(85)90082-1}, abstractNote={Gentamicin pharmacokinetics and nephrotoxicity have not been widely studied in animals with preexisting renal dysfunction, despite the fact that nephrotoxicity is a continuing manifestation of clinical therapy. The present study contrasted the dose-response nephrotoxicity of gentamicin in control rats with that of rats with renal insufficiency secondary to subtotal (2/3) surgical nephrectomy. Total daily doses ranging from 0 to 120 mg/kg were given in a divided regimen, every 8 hr and doses were reduced by doubling the interval in subtotally nephrectomized (Nx) rats, in proportion to impaired renal elimination on the first day of gentamicin administration. Estimates of renal function, including creatinine clearance, fractional sodium and potassium excretion, and serum creatinine and urea nitrogen, were collected after 6 and 12 days of dosing. In addition, urinary N-acetyl-beta-D-glucosaminidase excretion (6 days), in vitro renal cortical slice accumulation of tetraethylammonium (TEA) (6 days), quantified morphological lesions (12 days), and renal gentamicin concentrations (6 days) were examined. Pharmacokinetic data collected immediately after the first dose revealed a reduced gentamicin clearance and slightly reduced volume of distribution, with a corresponding prolonged half-life in the Nx rats. Based on statistical analysis of the dose-response relationships, Nx rats were functionally resistant to gentamicin nephrotoxicity after 6 days of dosing. This resistance was partially reversed by 12 days dosing, despite light-microscopic evidence of greater structural damage in the control rats. Renal parenchymal gentamicin concentrations were lower at some doses in the Nx rats, in contrast to the higher fractional reabsorption found in these rats at all doses. TEA transport was depressed at all doses in control rats but not at the lower doses in Nx rats, indicating that resistance was partially mediated at the level of the proximal tubular epithelium. This study demonstrates altered gentamicin pharmacokinetics and nephrotoxicity in a surgical model of renal dysfunction in rats.}, number={2}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={CARVER, MP and SHYMODJESKA, JS and BROWN, TT and ROGERS, RA and RIVIERE, JE}, year={1985}, pages={251–263} }
 @inproceedings{riviere_carver_1985, title={Effects of pre-existing renal disease on aminoglycoside nephrotoxicity in dogs and rats}, ISBN={0471907405}, booktitle={Renal heterogeneity and target cell toxicity : proceedings of the Second International Symposium on Nephrotoxicity, University of Surrey, UK, 6-9 August 1984}, publisher={Chichester: John Wiley and Sons Ltd.}, author={Riviere, J. E. and Carver, M. P.}, year={1985}, pages={339–344} }
 @article{riviere_carver_1984, title={Effects of familial hypothyroidism and subtotal surgical nephrectomy on gentamicin pharmacokinetics in beagle dogs}, volume={30}, DOI={10.1159/000238271}, abstractNote={Gentamicin serum pharmacokinetics were studied in normal, subtotally nephrectomized, and familial hypothyroid beagle dogs. Length of the gamma phase was not affected by subtotal nephrectomy but was shorter or almost nonexistent in hypothyroid dogs.}, journal={Chemotherapy}, author={Riviere, J. E. and Carver, M. P.}, year={1984}, pages={216–220} }
 @article{riviere_carver_coppoc_carlton_lantz_shymodjeska_1984, title={PHARMACOKINETICS AND COMPARATIVE NEPHROTOXICITY OF FIXED-DOSE VERSUS FIXED-INTERVAL REDUCTION OF GENTAMICIN DOSAGE IN SUBTOTAL NEPHRECTOMIZED DOGS}, volume={75}, ISSN={["1096-0333"]}, DOI={10.1016/0041-008X(84)90186-8}, abstractNote={There is presently no consensus as to the relative safety of fixed-interval/reduced dose (FI) vs fixed-dose/increased interval (FD) dosage adjustment regimens for use in renal insufficiency. This study compared their nephrotoxic potential using gentamicin in beagle dogs with renal insufficiency secondary to subtotal surgical nephrectomy. Pharmacokinetic analysis in six dogs showed that this surgical procedure resulted in a decreased total body clearance of drug and a marginally contracted volume of the central compartment. An allometric analysis of gentamicin disposition in different species was used to derive a human-equivalent maximum canine nontoxic dose of 9 mg kg-1 day-1. Nephrotoxicity was detected by histopathologic analysis and changes in the pre- and post-drug treatment, creatinine clearance, and daily drug elimination rate constants. This allometric dose did not produce clinical toxicity in a control group of six dogs with intact kidneys given drug for 14 days. Dosage adjustments within the FI and FD groups were based on serum creatinine concentrations 10 days after surgery. Statistical analysis of morphological and functional parameters indicated that the FD method was significantly less toxic than the FI regimen.}, number={3}, journal={TOXICOLOGY AND APPLIED PHARMACOLOGY}, author={RIVIERE, JE and CARVER, MP and COPPOC, GL and CARLTON, WW and LANTZ, GC and SHYMODJESKA, J}, year={1984}, pages={496–509} }