Thesis (Ph.D.)--University of California, San Francisco, 2005. / Includes bibliographical references. Also available online.

Made available in DSpace on 2016-01-13T13:27:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-09-19. Added 1 bitstream(s) on 2016-01-13T13:33:28Z : No. of bitstreams: 1 000856429.pdf: 1307975 bytes, checksum: 34294ec81a6d27dee7b8b875a152935a (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Instituto Nacional de Ciência e Tecnologia para inovação farmacêutica (INCT-if ) / O composto 3-(2-cloro-6-fluorobenzil)-imidazolidina-2-4-diona - PT-31 GIRSUPAN, planejado pelo grupo de pesquisa da Universidade Federal de Pernambuco, apresenta perfil analgésico resultante da ativação do 2-adrenoceptor no sistema nervoso central. Ainda, quando administrado pela via intraperitoneal (i.p.), em camundongos (15 mg/kg), o produto apresenta efeito sinérgico com a morfina. O objetivo desse estudo foi investigar características físico-químicas, aspectos de toxicidade e de farmacocinética do composto PT-31 GIRSUPAN com potencial aplicação no tratamento de dor. Os ensaios realizados para o composto foram: determinação do coeficiente de partição (logP); estudo de estabilidade química in vitro e ex vivo (plasma de rato); avaliação do perfil farmacocinético em ratos wistar após administração intraperitoneal (i.p.) e oral em dose única (10 mg/kg), isolado e em associação com a morfina; avaliação da toxicidade hepática e renal em ratos wistar; e avaliação do potencial de dependência. Ainda, para realizar o estudo de estabilidade e farmacocinético foram desenvolvidos e validados métodos analíticos e bioanalíticos por HPLC/UV e por LCMS para a determinação do PT-31 GIRSUPAN em solução e em plasma de rato. A determinação do coeficiente de partição (logP) do composto PT-31 GIRSUPAN resultou em logP de 1,6±0,1 pelo método in silico e 1,2±0,1 pelo método shake flask. Os métodos analítico e bioanalítico desenvolvidos apresentaram limites de confiança para a finalidade proposta e os resultados de estabilidade química e ex vivo demonstraram que o composto foi estável nos pHs estudados (3,0 e 7,4) e em plasma de rato por 12 horas. Na análise farmacocinética do composto administrado isoladamente foi possível observar valor de clearance (Cl) semelhante entre as vias i.p. e oral, entretanto os parâmetros volume de distribuição (Vd = 0,978 vs 0,681 L/kg) e meia vida de... / The compound 3-(2-chloro-6-fluoro-benzyl)-imidazolidine-2,4-dione - GIRSUPAN PT-31 was designed by the research group of the Federal University of Pernambuco. The PT-31 GIRSUPAN has analgesic effect from the activation of 2-adrenoceptor in central nervous system. Still, when administered by intraperitoneal (ip) route in mice (15 mg/kg), the compound has synergistic effect with morphine. The aim of this study was to investigate the physicochemical properties, toxicity aspects and pharmacokinetic profile of the compound PT-31 GIRSUPAN with potential application in the treatment of pain. The tests for the compound were: determination of the partition coefficient (logP); study chemical stability in vitro (buffer) and ex vivo (rat plasma); evaluation of pharmacokinetic profile in Wistar rats after intraperitoneal and oral administrations in a single dose. The PT-31 GIRSUPAN was administered alone and in association with morphine to assessment of liver and kidney toxicity in Wistar rats, and to assessment of the potential for addiction. Moreover, to achieve the pharmacokinetic and stability studies were developed and validated HPLC methods with UV and mass detection, for the determination of PT-31 GIRSUPAN in solution and rat plasma. The logP of PT-31 GIRSUPAN was 1.6 ± 0.1 by in silico method and 1.2 ± 0.1 by shake flask method. The analytical and bioanalytical methods developed showed confidence limits appropriate for the intended purpose and the results of chemical stability and ex vivo demonstrated that the compound was stable in the evaluated pHs (3.0 and 7.4) and in the rat plasma, both by 12 hours. In pharmacokinetic analysis of the compound administered alone was observed clearance (Cl) similar between ip and oral routes, however the volume of distribution (0.978 and 0.681 L/kg) and elimination half-life (3.7 and 2.9 h) were significantly higher in oral administration (p<0,05). The association of the compound with morphine ...

Orientador : Rosângela Gonçalves Peccinini / Banca: Roberto Takashi Sudo / Banca: Thalita Pedroni Formariz Pilon / Banca: Jean Leandro dos Santos / Banca: Chung Man Chin / Resumo: O composto 3-(2-cloro-6-fluorobenzil)-imidazolidina-2-4-diona - PT-31 GIRSUPAN, planejado pelo grupo de pesquisa da Universidade Federal de Pernambuco, apresenta perfil analgésico resultante da ativação do 2-adrenoceptor no sistema nervoso central. Ainda, quando administrado pela via intraperitoneal (i.p.), em camundongos (15 mg/kg), o produto apresenta efeito sinérgico com a morfina. O objetivo desse estudo foi investigar características físico-químicas, aspectos de toxicidade e de farmacocinética do composto PT-31 GIRSUPAN com potencial aplicação no tratamento de dor. Os ensaios realizados para o composto foram: determinação do coeficiente de partição (logP); estudo de estabilidade química "in vitro" e "ex vivo" (plasma de rato); avaliação do perfil farmacocinético em ratos wistar após administração intraperitoneal (i.p.) e oral em dose única (10 mg/kg), isolado e em associação com a morfina; avaliação da toxicidade hepática e renal em ratos wistar; e avaliação do potencial de dependência. Ainda, para realizar o estudo de estabilidade e farmacocinético foram desenvolvidos e validados métodos analíticos e bioanalíticos por HPLC/UV e por LCMS para a determinação do PT-31 GIRSUPAN em solução e em plasma de rato. A determinação do coeficiente de partição (logP) do composto PT-31 GIRSUPAN resultou em logP de 1,6±0,1 pelo método in silico e 1,2±0,1 pelo método "shake flask". Os métodos analítico e bioanalítico desenvolvidos apresentaram limites de confiança para a finalidade proposta e os resultados de estabilidade química e "ex vivo" demonstraram que o composto foi estável nos pHs estudados (3,0 e 7,4) e em plasma de rato por 12 horas. Na análise farmacocinética do composto administrado isoladamente foi possível observar valor de clearance (Cl) semelhante entre as vias i.p. e oral, entretanto os parâmetros volume de distribuição (Vd = 0,978 vs 0,681 L/kg) e meia vida de... / Abstract: The compound 3-(2-chloro-6-fluoro-benzyl)-imidazolidine-2,4-dione - GIRSUPAN PT-31 was designed by the research group of the Federal University of Pernambuco. The PT-31 GIRSUPAN has analgesic effect from the activation of 2-adrenoceptor in central nervous system. Still, when administered by intraperitoneal (ip) route in mice (15 mg/kg), the compound has synergistic effect with morphine. The aim of this study was to investigate the physicochemical properties, toxicity aspects and pharmacokinetic profile of the compound PT-31 GIRSUPAN with potential application in the treatment of pain. The tests for the compound were: determination of the partition coefficient (logP); study chemical stability "in vitro" (buffer) and "ex vivo" (rat plasma); evaluation of pharmacokinetic profile in Wistar rats after intraperitoneal and oral administrations in a single dose. The PT-31 GIRSUPAN was administered alone and in association with morphine to assessment of liver and kidney toxicity in Wistar rats, and to assessment of the potential for addiction. Moreover, to achieve the pharmacokinetic and stability studies were developed and validated HPLC methods with UV and mass detection, for the determination of PT-31 GIRSUPAN in solution and rat plasma. The logP of PT-31 GIRSUPAN was 1.6 ± 0.1 by in silico method and 1.2 ± 0.1 by shake flask method. The analytical and bioanalytical methods developed showed confidence limits appropriate for the intended purpose and the results of chemical stability and "ex vivo" demonstrated that the compound was stable in the evaluated pHs (3.0 and 7.4) and in the rat plasma, both by 12 hours. In pharmacokinetic analysis of the compound administered alone was observed clearance (Cl) similar between ip and oral routes, however the volume of distribution (0.978 and 0.681 L/kg) and elimination half-life (3.7 and 2.9 h) were significantly higher in oral administration (p<0,05). The association of the compound with morphine ... / Doutor

Master of Science in Biomedical Sciences / Department of Clinical Sciences / Walter C. Renberg / OBJECTIVE: The purpose of the study reported here was to evaluate pharmacokinetics of cefazolin in dogs receiving a single IV injection of cefazolin (22 mg/kg) and dogs receiving simultaneous IV and IM injections of cefazolin (total dose, 44 mg/kg). METHODS: Twelve purpose-bred Beagles (6/group) were assigned to receive a single injection of cefazolin (22 mg/kg, IV) or simultaneous injections (22 mg/kg, IV, and 22 mg/kg, IM). Interstitial fluid was collected over a 5-hour period using ultrafiltration probes for pharmacokinetic analysis. RESULTS: Mean cefazolin concentration in the interstitial fluid at 1, 1.5, 2, 3, 4, and 5 hours after injection was 39.6, 29.1, 21.1, 10.3, 6.4, and 2.7 μg/mL, respectively, for the IV group and 38.3, 53.3, 46.4, 31.7, 19.1, and 8.9 μg/mL, respectively, for the IV + IM group. The mean area under the concentration-time curve extrapolated to infinity, maximum concentration, half life and time to the maximum concentration was 74.99 and 154.16 h•μg/mL, 37.3 and 51.5 μg/mL, 0.96 and 1.11 hours, 1.28 and 1.65 hours, respectively, for the IV and IV + IM groups. CONCLUSIONS AND CLINICAL RELEVANCE: Cefazolin concentrations in interstitial fluid of dogs were maintained at > 4 μg/mL for 4 hours after a single IV injection and for 5 hours after simultaneous IV and IM injections. Based on these results, simultaneous administration of cefazolin IV + IM 30 to 60 minutes before surgery should provide interstitial fluid concentrations effective against the most common commensal organisms (Staphylococcus spp and Streptococcus spp) on the skin of dogs for surgical procedures lasting ≤ 4 hours.

PEP activity has been described in several locations and has mostly been linked to a variety of neurological disorders such as schizophrenia, amnaesia, depression as well as other disease states such as anorexia nervosa, bulimia nervosa and blood pressure regulation. The enzyme has also been previously isolated from a variety of archae, microorganisms and several eukaryotic species but no prolyl endopeptidases have been isolated from plants. Plants have high levels of proline and glutamine rich peptides in seeds. We therefore hypothesize plants must express PEPs during germination. Bioinformatics tools were used to identify known PEPs and putative plant PEPs. A global sequence alignment of putative plant PEPs and other known PEPs indicated that the active site amino acids Ser, His and Asp are conserved in putative plant PEP sequences. Furthermore, putative plant PEPs showed similar secondary structures to known PEPs and when a rice PEP was modelled onto porcine brain PEP structure, a high degree of similarity was found. Germination studies of wheat seed showed an increase of PEP activity over time with maximum PEP activity reached after 4 days of germination, which remained at this level until 9 days of germination, implying a function for PEP in plant seed germination. Wheat PEP was purified using ion exchange and gel filtration chromatography with a final yield of less than 1 percent and a relative purity (only 2 bands detected by SDS-PAGE). The purified wheat PEP had a molecular weight of approximately 55kDa, substrate specificity for chymotrypsin-like substrates (N-Suc-Ala-Ala-Pro-Phe-pNa, Km value of 0.58 mM, Kcat of 29.37 s–1; Kcat /Km 50813.14s–1 M–1); a pH optimum of 7.9; temperature optima of 37oC and a high sensitivity to temperature as indicated by loss of activity at temperatures above 40oC. Inhibition studies using E64, Leupeptin and PMSF confirmed that the wheat PEP is from the Serine protease family and is most likely a trypsin-like protease.

Pulmonary infections in critically ill patients are common, frequently lethal and treatment may be complicated by bacterial resistance. Piperacillin-tazobactam (PTZ) is a broad-spectrum β-lactam antibiotic, frequently used for pulmonary infections. Lung antibiotic concentration reflects target site concentrations in patients with pneumonia. Critically ill patient’s exhibit marked pharmacokinetic (PK) variability. PTZ exposures resulting in maximal bacterial killing and prevention of emergence of drug resistance are not known. Administration of PTZ by extended infusions (EI) or using Bayesian dosage optimisation, instead of a fixed bolus regimen, may improve clinical outcomes. Experimental work was conducted in an in vitro hollow fibre infection model (HFIM) using two densities of Pseudomonas aeruginosa. Experimental data was described by a mathematical model allowing identification of PTZ exposures associated with bacterial killing and suppression of the emergence of resistance. The population PK of PTZ in the plasma and lung of 17 critically ill patients was estimated. Monte Carlo simulation was used to explore the proportion of patients that achieve the plasma and lung PTZ exposures associated with bacterial killing and resistance suppression and to determine the effect of administration schedule. Finally, the population PK of PTZ in the plasma of 146 critically ill patients was estimated and used to construct computer software that can individualise PTZ dosing. Precision of the dosing software was assessed in 8 additional individuals. At low bacterial density a trough piperacillin:MIC ratio of 3.4 for bolus and 10.4 for EI regimens were able to suppress the emergence of resistance. At higher bacterial density all regimens were associated with growth of a resistant sub-population. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated to pulmonary permeability. Simulations revealed that EI, compared with bolus dosing, of PTZ is associated with a higher likelihood of bacteria killing. Similar probability of developing resistance was predicted with PTZ administration by EI and by bolus administration. Performance of the dose optimisation software was satisfactory. Current PTZ regimens are insufficient to treat pneumonia in approximately 14% of critically ill patients. Delivery of PTZ by EI may be a more effective method of administration for some patients with nosocomial infections. Individualised PTZ regimens, delivering a target piperacillin concentration, identified in a HFIM, are achievable and should improved clinical outcomes. Patients with a high bacterial burden may required alternative therapeutic strategies to maximize bacterial killing and prevent antimicrobial resistance.

The anticonvulsant drug valproic acid (VPA) is extensively metabolized with 16 metabolites identified in man. Of interest are the unsaturated metabolites which appear to be responsible for the observed secondary antiepileptic activity and/or idiosyncratic hepatotoxicity. A study by Abbott et al . (1986) has shown 2-((E)-1'-propenyl)-(E)-2-pentenoic acid ((E,E)-2,3'-diene VPA) to be a major unsaturated metabolite of VPA. Acheampong (1985) demonstrated that an isomeric mixture of 2,3'-diene VPA prevented pentylenetetrazole-induced seizures in mice and had 60% the potency of VPA. Research on (E,E)-2,3'-diene VPA is limited even though the diene appears to be a contributor to the secondary antiepileptic effect. Available synthesis of 2,3'-diene VPA result in two or more isomers with very low yields as shown by Acheampong and Abbott (1985). The object of this work was, therefore, to synthesize (E,E)-2,3'-diene VPA in sufficient quantity and isomeric purity for metabolic and pharmacokinetic studies in rats. Synthesis of (E,E)-2,3'-diene VPA was achieved by the alkylation of ethyl (Z)-2-pentenoate to afford ethyl 2-(l'-hydroxypropyl)-(E)-2-pentenoate. Dehydration using methanesulfonyl chloride and potassium hydride gave the ethyl ester of (E,E)-2,3'-diene VPA. Hydrolysis of the ester in 1 N NaOH afforded an 81.2% pure sample of (E,E)- 2,3'-diene VPA as determined by GCMS and NMR. A second method was used to unequivocally synthesize (E,E)-2,3' - diene VPA whereby an O-trimethylsilylketene acetal was oxidized via a hydride abstractor to yield two isomers of 2,3'-diene VPA plus the starting material (E)-3-ene VPA. The identity of the products were determined by GCMS with the major isomer being (E,E)-2,3'-diene VPA. In the metabolism studies, Wistar rats were given 100 mg/kg i.p. of (E,E)-2,3'-diene VPA and bile and urine collected for 24 hours. GCMS analysis revealed three metabolites present in both bile and urine. These were reduction products of (E,E)-2,3'-diene VPA metabolism and consisted of the monounsatured (E)-3-ene VPA and (E)-2-ene VPA plus the fully saturated VPA. These results suggest that trace levels of (E)-3-ene VPA observed after VPA dosing may not be a direct metabolic product of VPA itself but rather a reduced metabolite of (E,E)-2,3'-diene VPA. All polar metabolites are yet to be identified. For the pharmacokinetic studies, two doses, 20 and 100 mg/kg of (E,E)-2,3'-diene VPA were administered i.v. to Wistar rats and the plasma concentration vs time decline curve determined using GCMS analysis of the plasma samples. The bile duct of these animals was then cannulated and the study repeated. A comparison between the elimination rate constant (KE), clearance (C1), and volume of distribution (Vd) between the bile duct intact and cannulated rats for both dose groups revealed no significant differences (p>0.1). A comparison of the KE, Vd, and C1 between dosage groups of both bile duct intact and cannulated rats revealed no significant difference (p>0.08-0.7). Therefore, extensive enterohepatic recirculation was not apparent and the elimination of (E,E)-2,3'-diene VPA appeared to be dose-independent. The diene seems to follow a simple one-compartment model with a half-life of 35.9±8.9 (S.D.) minutes and a large volume of distribution of 0.95±0.22 (S.D.) L/kg. In vitro protein binding studies revealed that (E,E)-2,3'-diene VPA saturates plasma proteins between concentrations of 30 - 600 ug/mL. The percent of (E,E)-2,3'-diene VPA bound decreases from 92.1% to 28.7% as the concentration of diene increases suggesting concentration-dependent protein binding. The synthesis of (E,E)-2,3'-diene VPA in substantial quantities has allowed metabolic and pharmacokinetic studies to be performed in rats. Preliminary studies showed that (E,E)-2,3' -diene VPA was metabolically reduced to monounsaturated and saturated products. Pharmacokinetic data appear to indicate a potential for the diene to accumulate in the central nervous system. Further studies are required to determine the contribution of (E,E)-2,3'-diene VPA to the secondary antiepileptic activity of VPA. / Pharmaceutical Sciences, Faculty of / Graduate

The role of noradrenaline (NA) in the behavioural and pharmacological effects of morphine was evaluated in rats. Animals received specific injections of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DB) resulting in selective depletion of telencephalic NA levels and increased levels of noradrenaline in the spinal cord and cerebellum. Employing changes in the hypoactive phase of morphine-induced locomotor activity as an index of tolerance development, it was observed that injection of 6-OHDA into the dorsal noradrenergic bundle resulted in a slower rate and a lesser degree of tolerance development to morphine. The effect of the DB-6-0HDA lesion on physical dependence was assessed by measuring naltrexone-induced withdrawal in lesioned and control animals who had received chronic morphine treatment. Results indicate that although NA is important in tolerance development, it does not mediate a dominant role in withdrawal, although behavioural evidence suggesting a secondary or modulatory role is presented. The interaction of amphetamine and morphine with the dopamine (DA) system was also assessed by studying the behavioural effects of amphetamine in animals following either acute or chronic morphine treatment. It was observed that amphetamine potentiated the spontaneous locomotor hyperactivity following both acute and chronic morphine treatment. The DB-6-OHDA lesion did not affect the locomotor potentiation of amphetamine in morphine pre-treated animals, and the hypothesis that another transmitter system mediates this effect, specifically DA, is discussed. / Medicine, Faculty of / Graduate

An evaluation of vancomycin pharmacokinetics was performed in 2 phases. In phase I, a vancomycin population pharmacokinetic model was developed based on data from 126 patients using a two-compartment model. Variables tested for inclusion in the model were creatinine clearance (Crcl), age, total body weight (wt) ICU status, gender, body surface area, ideal weight and height. Variables were included at the P < _ 0. 05 level. The final population pharmacokinetic model was as follows: Cl (L/hr) = (0.025 * Crcl) * (1 + 0.0165 *age), V1 (L) = 29.5, V2 (L) = 8.17 + 0.349 * Crcl and Q (L/hr.kg) = 0. 0639 * wt. For ICU patients, V2 was larger than the non ICU patients and it was V2 (L) = 16.258 + 0.694 * Crcl. In phase II, the performance of the derived model was evaluated and compared to the Moellering, Matzke, Birt & Chandler and Rodvold Methods. Predictability of .52 vancomycin serum concentrations was assessed in 3 0 new patients. In predicting all concentration types, mean prediction error (MPE) with 95% CI for Moellering,. Matzke, Birt & Chandler, Rodvold and current methods were -0.1 (-1.6, 1.4), -0.8 (-0.7, 2. 4) , o. o ( -1.5, 1. 6) , -2. 0 ( -3. 4, -o. 5) , and 2. 1 ( o. 9, 3. 4) mg/L respectively. When considering only troughs, MPE with 95% CI were 1.8 (0.2, 3.4), 2.7 (0.9, 4.6), -1.5 (-3.5, 0.5), -1.5 (-3.2, 0.1), and 0.8 (-0.8, 2.4) mg/L respectively. MPE with 95% for the peaks were -2.5 (-5.0, 0.0), -1.6 (-4.1, 1.0), 2.0 (-0.4, 4.4), -2.5 (-5.3, 0.3) and 3.8 (1.8, 5.8) mg/L respectively. Median absolute prediction error (MABPE) , 5% and 95% quantiles for all concentration types for Moellering, Matzke, Birt & Chandler, Rodvold and current methods were 3.4 (0.2, 10.1), 4.1 (0.3, 10.9), 3.9 (0.4, 11.7), 3.1 (0.2, 13.0) and 2.3 (0.1, 9.5) mg/L respectively. MABPE, 5% and 95% quantiles for the troughs were 2. 6 ( o. 2, 9. 4) , 4. o ( o. 4, 10. 3) , 4. 1 (0.7, 10.2), 2.9 (0.2, 9.4) and 2.0 (0.1, 9.2) mg/L respectively. MABPE, 5% and 95% quantiles for the peaks were 5.0 (0.7, 11.5·), 4.2 (0.3, 10.9), 3.8 (0.4, 11.7), 4.9 (0.6, 13.0) and 5.0 (1.1, 9.5) mg/L respectively. It is recommended that the current method be used while setting initial target peak at 30 mg/L with the initial target trough at 6 mgjL. This should frequently result in serum vancomycin concentration within the therapeutic window. Individualization of therapy should then be done when the measured concentrations are available.

Approximately 10 years ago, “bath salts” were popularized as legal alternatives to the psychostimulants cocaine and the amphetamines, circumventing legislation with packages marked, “not for human consumption.” These products contained synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). The synthetic cathinones have similar pharmacology to controlled psychostimulants, increasing levels of dopamine (DA) in the synaptic cleft, while also exhibiting similar psychoactive effects such as increased energy and euphoria. Additionally, adverse effects of “bath salts” are similar to controlled psychostimulants, such as chest pain, shortness of breath, and hallucinations. Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and DEA studies indicate that “bath salts” contain mixtures of these substances. Therefore, in a recent study by our laboratory, we examined effects of individual versus combined exposure to MDPV, mephedrone, and methylone. Interestingly, an enhanced effect on the levels of DA in a number of brain regions was observed, as well as significant alterations in locomotor activity following co-exposure to the cathinones. Here, we examine if the enhanced effects of the drug combination are due to pharmacokinetic (PK) interactions. Many of the same cytochrome isoenzymes metabolize each of these 3 drugs; thus, it is probable that the drugs’ PK would differ when administered individually as compared to in combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased total drug concentrations when compared to individual administration. Briefly, adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at the following time points: 1, 10, 15, 30, 60, and 120 minutes. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high pressure-liquid chromatography tandem mass spectrometry method. All drugs quickly crossed the blood-brain barrier and entered the brain. PK data for methylone and mephedrone was consistent with our hypothesis. For methylone, the maximal concentration (Cmax) and the total drug exposure (as represented by the area under the curve (AUC)) were significantly higher when combined with mephedrone and MDPV in both matrices. For mephedrone, the Cmax was unchanged, but AUC in brain was increased when combined with the other two drugs. However, interestingly, for MDPV, the Cmax was unchanged, yet the AUC in brain was higher when MDPV was administered individually. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular “bath salt” products.