Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.

OBJECTIVE: To assess whether dose escalation (ie, doubling the dose) of emergency contraception that contains levonorgestrel (LNG) improves pharmacodynamic outcomes in individuals with obesity. METHODS: We enrolled healthy, reproductive-age individuals with regular menstrual cycles, body mass index (BMI) higher than 30, and weight at least 176 lbs in a randomized pharmacodynamic study. After confirming ovulation (luteal progesterone level greater than 3 ng/mL), we monitored participants with transvaginal ultrasonography and blood sampling for progesterone, luteinizing hormone, and estradiol every other day until a dominant follicle measuring 15 mm or greater was visualized. At that point, participants received either oral emergency contraception with LNG 1.5 mg or 3 mg (double dose) and returned for daily monitoring for up to 7 days. Our primary outcome was the difference in the proportion of participants with no follicle rupture 5 days postdosing (yes or no) between groups. The study had 80% power to detect a 30% difference in the proportion of cycles with at least a 5-day delay in follicle rupture (50% decrease). RESULTS: A total of 70 enrolled and completed study procedures. The two groups had similar baseline demographics (mean age 28 years, BMI 38). We found no difference between groups in the proportion of participants without follicle rupture more than 5 days post-LNG dosing (LNG 1.5 mg: 18/35 [51.4%]; LNG 3.0 mg: 24/35 [68.6%], P=.14). Among participants with follicle rupture before 5 days, the time to rupture did not differ between groups (day at 75% probability of no rupture is day 2 for both groups). CONCLUSION: Individuals with higher BMIs and weights experience a higher risk of failure of emergency contraception with LNG and exhibit an altered pharmacokinetic profile. However, the simple strategy of doubling the dose does not appear to be an effective intervention to improve outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, 02859337.

Ziritaxestat Drug-Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition.

In vitro signals indicate that ziritaxestat is a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with oral contraceptives were examined at a time when ziritaxestat was under development for treatment of fibrotic diseases. This open-label, crossover (fixed sequence) DDI study enrolled healthy, nonpregnant women aged 18-65 years (n = 15) who were using highly effective contraception, such as a nonhormonal intrauterine device, bilateral tubal occlusion, or sexual abstinence. A single dose of oral contraceptive (0.03 mg ethinyl estradiol (EE) and 3 mg drospirenone (DRSP)) was administered on days 1, 8, and 18, and ziritaxestat 600 mg once daily was administered from days 8 to 23. Co-administration resulted in a 2.8-fold and 2.4-fold increase in EE maximum plasma concentration (Cmax ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC0-inf ), respectively (day 18 vs. day 1). DRSP Cmax and AUC0-inf increased by 1.1-fold and 1.2-fold, respectively. DRSP is a CYP3A4 substrate, meaning increased EE exposure with ziritaxestat was not due to CYP3A4 inhibition. Ziritaxestat inhibition of EE glucuronidation and sulfation was quantified by liquid chromatography with tandem mass spectrometry in day 1 and day 18 plasma samples after EE conjugate hydrolysis. The ratio of EE AUC from time of administration up to the time of the last quantifiable concentration (AUClast ) with/without hydrolysis by arylsulfatase was substantially lower on day 18 vs. day 1, suggesting ziritaxestat is a potent inhibitor of sulfation; EE glucuronidation was largely unaffected by ziritaxestat. In vitro assessment confirmed ziritaxestat is a potent inhibitor of sulfotransferase family 1E member 1 (half-maximal inhibitory concentration < 0.8 µM). These findings highlight the importance of assessing enzymes other than CYP3A4 when investigating potential DDIs with oral contraceptives.

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.

Evaluation of the potential for pharmacokinetic interaction between tirabrutinib and levonorgestrel/ethinyl estradiol in healthy female volunteers.

Tirabrutinib (TIRA), a potent and nonreversible oral Bruton tyrosine kinase inhibitor, is evaluated for treatment of certain hematological malignancies and inflammatory diseases. A drug-drug interaction study to evaluate the effect of TIRA on the pharmacokinetics of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted in healthy female participants (N = 26). Participants received a single dose of LEVO (150 mcg)/EE (30 mcg) alone (reference), and on day 12 of a 15-day regimen of TIRA 160 mg once-daily (test). Intensive blood sampling for determination of LEVO, EE, and TIRA plasma concentrations was conducted, and safety was assessed throughout the study. Pharmacokinetic interactions were evaluated using 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of the test versus reference treatments. The GLSM (90% CI) ratios of area under the concentration-time curve from zero to infinity (AUCinf ; LEVO: 0.95, 95% CI: 0.88-1.03, EE: 1.10, 95% CI: 1.05-1.16) and maximum plasma concentration (Cmax ; LEVO: 0.85, 95% CI: 0.74-0.98, EE: 1.07, 95% CI: 0.98-1.18) were within the prespecified 0.70 to 1.43 no effect bounds; and the AUC ratios met the stricter 0.80 to 1.25 equivalence bounds. Study treatments were generally well-tolerated. In conclusion, co-administration with TIRA did not alter the exposure of LEVO/EE, and accordingly LEVO/EE containing oral contraceptives can serve as a contraception method for participants on TIRA 160 mg (or lower) daily doses.

Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: a pilot study.

BACKGROUND: We performed a pilot evaluation of a new formulation of levonorgestrel butanoate (LB) designed to be a long-acting injectable (6 months) contraceptive to determine pharmacodynamic end points in normal-body mass index (BMI) and obese women. STUDY DESIGN: Obese (BMI ≥30 kg/m2) and normal-BMI, otherwise healthy, women received a single intramuscular injection of LB after ovulation was confirmed in a baseline cycle. The primary outcome was return of ovulation in days. RESULTS: A total of 14 women enrolled and completed the study [normal BMI n=9, median BMI 22.7kg/m2 (range 19.4-25.8); obese n=5, median BMI 35.7kg/m2 (30.1-39.2)]. The first 6 subjects (normal BMI=4/9, obese BMI=2/5) received 40 mg of LB, and the remaining 8 received 20 mg. All women except one returned to ovulation prior to 6 months. Return to ovulation occurred earlier in the obese group; 3/5 obese and 0/9 normal BMI subjects returned to ovulation within 90 days (p=.03). No serious adverse events were reported during the study. CONCLUSION: Return to ovulation was earlier than 6 months in both BMI groups but more so in the obese BMI group. IMPLICATIONS: Since return of ovulation was earlier than expected for this LB injectable formulation, additional steps are needed to develop a preparation suitable as a longer-lasting product.

Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.

OBJECTIVE: To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations. STUDY DESIGN: Healthy, reproductive-age women with obese and normal BMIs received 1.5mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2). Dosing occurred during the follicular phase. Total and free LNG PK parameters were obtained via serum samples through an indwelling catheter at 0, 0.5, 1, 1.5, 2, and 2.5h. The primary outcome was the difference in total and free LNG concentration maximum (Cmax) between ECx1 and ECx2 in the obese group. RESULTS: A total of 10 women enrolled and completed the study (normal BMI=5, median 22.8kg/m(2), range 20.8-23.7; obese BMI=5, 39.5kg/m(2), range 35.9-46.7). The total LNG Cmax for obese subjects following ECx1 (5.57±2.48ng/mL) was significantly lower than the level observed in normal BMI women (10.30±2.47, p=.027). Notably, ECx2 increased the Cmax significantly (10.52±2.76, p=.002); approximating the level in normal BMI subjects receiving ECx1. Free LNG Cmax followed a similar pattern. CONCLUSION: Obesity adversely impacts both the total and free Cmax levels of LNG EC and this likely explains its lack of efficacy in obese women. Doubling the dose appears to correct the obesity-related PK changes but additional research is needed to determine if this also improves EC effectiveness in obese women. IMPLICATIONS: This study demonstrates that obesity interferes with the pharmacokinetics of LNG EC, and that doubling the dose may be an effective strategy to improve its efficacy in obese women.

Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post-Weaning High-Fat Diet.

Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We suggested that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low-protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or high-fat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a ~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high-fat diet trended in the opposite direction to that of IUGR, with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half-life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters 1 and 3, and sodium-potassium-chloride cotransporter-2. In summary, this study suggests that IUGR and diet interact to produce subpopulations with similar body-weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one-size-fits-all dosing which does not account for physiological differences in body composition resulting from IUGR and diet.

Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver.

Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60 mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non-compartmental pharmacokinetic parameters were as follows: half-life 7.37 ± 1.22 hr; volume of distribution 44.62 ± 11.45 L; area under the curve 14.82 ± 2.71 hr/(µg/mL); and clearance 4.15 ± 0.70 L/hr. Rapid theophylline distribution across the placenta was observed. Maternal non-compartmental pharmacokinetic parameters were as follows: half-life 6.54 ± 2.44 hr; volume of distribution 32.48 ± 9.99 L; area under the curve 16.28 ± 4.53 hr/(µg/mL); and clearance 3.69 ± 1.47 L/hr. Foetal and ewe serum concentration-time profiles were fit together into a 3-compartment population pharmacokinetic model, and parameters were as follows: central volume 1.38 ± 0.11 L; 2nd peripheral compartment volume 3.11 ± 0.29 L; 3rd peripheral compartment volume 60.14 ± 6.02 L; elimination clearance 9.89 ± 0.90 L/hr; distribution clearance between central and 2nd compartment 30.87 ± 2.31 L/hr; and distribution clearance between 2nd and 3rd compartments 13.89 ± 1.11 L/hr. Cytochrome P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7 ± 4.4 versus 42.0 ± 3.6%-bound). Free concentrations were lower in the foetus than in the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity.

Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy.

OBJECTIVE: Pharmacokinetics of norethindrone in combination oral contraceptive regimen are well described among HIV+ women treated with ritonavir-boosted protease inhibitor therapies; however, such characterization is lacking in women using progestin-only contraception. Our objective is to characterize pharmacokinetics of norethindrone in HIV+ women using ritonavir-boosted atazanavir treatment during progestin-only contraceptive regimens. STUDY DESIGN: An open-label, prospective, nonrandomized trial to characterize the pharmacokinetics of norethindrone in HIV+ women receiving ritonavir-boosted atazanavir (n=10; treatment group) and other antiretroviral therapy known to not alter norethindrone levels (n=17; control group) was conducted. Following informed consent, women were instructed to take a single daily fixed oral dose of 0.35 mg norethindrone and 300 mg/100 mg atazanavir/ritonavir for 22 days. On day 22, serial blood samples were collected by venous catheter at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h. Whole blood was processed to collect serum and stored at -20°C until later analysis using radioimmunoassay. Pharmacokinetic parameters were estimated using noncompartmental method. RESULTS: In the treatment group, compared to the control group, an increase in area under the curve0₋24 (16.69 h*ng/mL vs. 25.20 h*ng/mL; p<.05) and maximum serum concentration (2.09 ng/mL vs. 3.19 ng/mL; p<.05), decrease (25%-40%) in apparent volume of distribution and apparent clearance, and unaltered half-life were observed. CONCLUSION(S): Our findings suggest that progestin-only contraceptives, unlike combination oral contraceptives, benefit from drug-drug interaction and achieve higher levels of exposure. Further studies are needed to establish whether pharmacokinetic interaction leads to favorable clinical outcomes. IMPLICATIONS: Norethindrone-based progestin-only contraceptives, unlike combination oral contraceptives, exhibit greater drug exposure when co-administered with ritonavir-boosted atazanavir regimen and thus may not warrant a category 3 designation by the World Health Organization. Prospective studies are needed to confirm whether pharmacokinetic interaction results in favorable clinical outcomes.

How can we improve oral contraceptive success in obese women?

A rapid increase in obesity rates worldwide further underscores the importance of better understanding the pharmacokinetic alterations in this sub-population and the subsequent effects on pharmacotherapeutics. Pharmacokinetics of contraceptive steroids is altered in obese oral contraceptive users, which may in turn impact efficacy. Our study has identified several dosing strategies that offset these pharmacokinetic changes and may improve effectiveness for obese oral contraception users.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

INTRODUCTION: Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. PURPOSE: Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. METHODS: We treated 20 patients who had recurrent prostate cancer with 200 µmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 µmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial.

OBJECTIVE: To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use. STUDY DESIGN: Obese [body mass index (BMI)≥30 kg/m(2)], ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to the following: continuous cycling (CC, a dose neutral arm using the same OC with no hormone-free interval) or increased dose (ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically). During Cycles 2, 3 and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞) and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles. RESULTS: A total of 31 women enrolled and completed the study (CC group, n=16; ID group, n=15). Demographics were similar between groups [mean BMI: CC, 38 kg/m(2) (S.D. 5.1); ID, 41 kg/m(2) (S.D. 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady state was 12 days in both groups; Cmax were CC: 3.82±1.28 ng/mL and ID: 3.13±0.87 ng/mL; and AUC0-∞ were CC: 267±115 h ng/mL and ID: 199±75 h ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p<.001) but again required 12 days to achieve steady state. However, AUC was not significantly different between CC (412±255 h ng/mL) and ID (283±130 h ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31). CONCLUSION: Both increasing the OC dose and continuous dosing appear to counteract the impact of obesity on key OC PK parameters. IMPLICATIONS: Obesity adversely affects the pharmacokinetics of very low dose OC pills. Although the impact of these changes on OC efficacy is still under debate, PK parameters can be normalized in obese users by continuous dosing or increasing to a low-dose pill.

Are children undergoing cardiac surgery receiving antibiotics at subtherapeutic levels?

OBJECTIVES: Perioperative antibiotics have decreased-but not eradicated-postoperative infections. In patients undergoing cardiac surgery with cardiopulmonary bypass, the dilutional effect of the priming and any additional volume given during the procedure may lead to subtherapeutic antibiotic levels. Our aim was to determine if children undergoing cardiac surgery with cardiopulmonary bypass receive perioperative antibiotics at subtherapeutic levels. METHODS: Using published pharmacokinetic data on cefuroxime, we developed a computer simulation model to generate a nomogram predicting patients at risk for subtherapeutic cefuroxime levels based on time from initial dosing and additional volume given. RESULTS: A computer-generated 1-compartment pharmacokinetic model was created to predict cefuroxime plasma levels over time for patients of all weights and additional volumes given for both a 25- and 50-mg/kg intravenous dose. For example, following a 25-mg/kg dose, a patient receiving an additional volume of 275 mL/kg is predicted to be subtherapeutic (<16 mg/L=4×minimum inhibitory concentration) at 4 hours. Our nomogram predicts all patients will be subtherapeutic at 8 hours, consistent with general pediatrics dosing schemes. Following a 50-mg/kg dose, levels are predicted to be subtherapeutic after an additional volume of 315 mL/kg at 5.5 hours. CONCLUSIONS: Our model predicts which patients undergoing cardiac surgery with cardiopulmonary will have subtherapeutic cefuroxime levels. This nomogram enables providers to determine when to administer additional antibiotics in patients receiving large additional volumes during cardiac surgeries. This rational approach to perioperative antibiotic dosing may result in a reduction in postoperative infection in this vulnerable patient population.

Perinatal growth restriction decreases diuretic action of furosemide in adult rats.

Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2mg/kg single i.p. dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis were similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters were unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response.