Phase I Study of Paclitaxel in Combination With a Multidrug Resistance Modulator, PSC 833 (Valspodar), in Refractory Malignancies

2000 ◽  
Vol 18 (5) ◽  
pp. 1124-1124 ◽  
Author(s):  
Paula M. Fracasso ◽  
Peter Westerveldt ◽  
Carole A. Fears ◽  
D. Marc Rosen ◽  
Eleanor G. Zuhowski ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Terminal Phase ◽  
Time Curve ◽  
Blood Concentrations ◽  
Psc 833 ◽  
Starting Dose ◽  
Disease Stabilization ◽  
Paclitaxel Treatment

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of paclitaxel when given with PSC 833 (valspodar) to patients with refractory solid tumors. PATIENTS AND METHODS: Patients were initially treated with paclitaxel 175 mg/m2 continuous intravenous infusion (CIVI) over 3 hours. Subsequently, 29 hours of treatment with CIVI PSC 833 was started 2 hours before paclitaxel treatment was initiated. In this combination, the starting dose of paclitaxel was 52.5 mg/m2. Paclitaxel doses were escalated by 17.5 mg/m2 increments for four subsequent cohorts. Each cohort consisted of three patients with the exception of the last cohort, which consisted of six patients. Data for the pharmacokinetics of paclitaxel with and without concurrent PSC 833 administration were obtained. RESULTS: All 18 patients completed at least one course of concurrent treatment (median, two courses; range, one to six) and were evaluable for toxicity. The MTD for paclitaxel with PSC 833 was 122.5 mg/m2. Neutropenia was the DLT. All patients had PSC 833 blood concentrations greater than 1,000 ng/mL before, during, and 24 hours after the paclitaxel infusion. PSC 833 produced small increases in the paclitaxel peak plasma concentrations and areas under the concentration-time curve. However, PSC 833 greatly prolonged the terminal phase of paclitaxel, resulting in plasma paclitaxel concentrations of more than 0.05 μmol/L for much longer than expected. As a result, myelosuppression was comparable to that produced by full-dose paclitaxel given without PSC 833. Of the 16 patients who were assessable for response, one patient experienced a partial response and an additional nine patients experienced disease stabilization after paclitaxel treatment alone. CONCLUSION: Treatment with paclitaxel 122.5 mg/m2 as a 3-hour CIVI concurrent with a 29-hour CIVI of PSC 833 results in acceptable toxicity. The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination.

Phase I Clinical and Pharmacokinetic Study of Flavopiridol in Children With Refractory Solid Tumors: A Children's Oncology Group Study

2005 ◽  
Vol 23 (36) ◽  
pp. 9179-9186 ◽  
Author(s):  
James A. Whitlock ◽  
Mark Krailo ◽  
Joel M. Reid ◽  
Stacie L. Ruben ◽  
Matthew M. Ames ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Starting Dose ◽  
Recommended Phase Ii Dose

Purpose To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors. Patients and Methods Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3. Results Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 μmol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2). Conclusion The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

scholarly journals Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis

2011 ◽  
Vol 55 (12) ◽  
pp. 5798-5803 ◽  
Author(s):  
O. A. Cornely ◽  
J. J. Vehreschild ◽  
M. J. G. T. Vehreschild ◽  
G. Würthwein ◽  
D. Arenz ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Peak Plasma ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Dose Escalation Study ◽  
Time Curve ◽  
Dose Limiting Toxicity

ABSTRACTOur objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.

scholarly journals Outcomes in treatment-resistant schizophrenia: symptoms, function and clozapine plasma concentrations

2021 ◽  
Vol 11 ◽  
pp. 204512532110371
Author(s):  
Amir Krivoy ◽  
Eromona Whiskey ◽  
Henrietta Webb-Wilson ◽  
Dan Joyce ◽  
Derek K. Tracy ◽  
...  
Keyword(s):  
Functional Outcome ◽  
Clinical Symptom ◽  
Clinical Improvement ◽  
Clinical Symptoms ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Symptom Improvement ◽  
Blood Concentrations ◽  
Treatment Refractory ◽  
The Relationship

Background: Clozapine is the only medication licenced for treating patients with treatment-refractory schizophrenia. However, there are no evidence-based guidelines as to the optimal plasma level of clozapine to aim for, and their association with clinical and functional outcome. Objective: We assessed the relationship between clinical and functional outcome measures and blood concentrations of clozapine among patients with treatment-refractory psychosis. Methods: Data were reviewed in 82 patients with treatment-refractory psychosis admitted to a specialised tertiary-level service and treated with clozapine. Analysis focussed on the relationship between clozapine and norclozapine plasma concentrations and the patient’s clinical symptoms and functional status. Results: Clinical symptom improvement was positively correlated with norclozapine plasma concentrations and inversely correlated with clozapine to norclozapine plasma concentrations ratio. Clozapine concentrations showed a bimodal association with clinical improvement (peaks around 350 and 660 ng/ml). Clinical symptom improvement correlated with functional outcomes, although there was no significant correlation between the latter and clozapine or norclozapine plasma concentrations. Conclusion: Clozapine treatment was associated with optimal clinical improvement at two different peak plasma concentrations around 350 and 650 ng/ml. Clinical improvement was associated with functional outcome; however, functionality was not directly associated with clozapine concentrations. A subset of patients may require higher clozapine plasma concentrations to achieve clinical improvement.

Exposure to Retinoic Acids in Non-Pregnant Women Following High Vitamin A Intake with a Liver Meal

2005 ◽  
Vol 75 (3) ◽  
pp. 187-194 ◽  
Author(s):  
Hartmann ◽  
Brørs ◽  
Bock ◽  
Blomhoff ◽  
Bausch ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Vitamin A ◽  
Safety Concern ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Pregnant Female ◽  
Time Curve ◽  
High Vitamin ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

1994 ◽  
Vol 12 (9) ◽  
pp. 1902-1909 ◽  
Author(s):  
D R Budman ◽  
L N Igwemezie ◽  
S Kaul ◽  
J Behr ◽  
S Lichtman ◽  
...  
Keyword(s):  
High Performance ◽  
Peak Plasma ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
High Dose ◽  
Maximum Plasma ◽  
Rapid Infusion ◽  
Etoposide Phosphate

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Pharmacokinetics (PK) of CR011-vcMMAE, an antibody-drug conjugate (ADC), in a phase (Ph) I study of patients (pts) with advanced melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9063-9063
Author(s):  
M. Sznol ◽  
O. Hamid ◽  
P. Hwu ◽  
H. Kluger ◽  
T. Hawthorne ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
Terminal Phase ◽  
Maximum Plasma ◽  
Additional Dose ◽  
Toxicity Data ◽  
Liquid Chromatography Mass Spectrometry ◽  
Antibody Drug Conjugate ◽  
Dose Limiting Toxicity

9063 Background: CR011-vcMMAE, an ADC of fully-human monoclonal anti-GPNMB antibody (Ab) with monomethylauristatin E (MMAE), is in Ph I/II trials in pts with melanoma and breast cancer. We report PK and toxicity data from a Ph I study in melanoma pts treated every (q) 3 weeks (w), qw, or 2 of 3w. Methods: Enzyme-linked immunosorbent assays were used to measure ADC, total Ab (TA), soluble GPNMB (sGPNMB), and anti-ADC Ab in pt samples. Free MMAE was measured by liquid chromatography/mass spectrometry. Results: Initially, 32 pts were treated in 9 cohorts of 0.03 to 2.63 mg/kg iv q3w using standard 3+3 dose escalation. Noncompartmental PK analysis showed dose-proportional TA, ADC and free MMAE levels. As previously reported, maximum tolerated dose (MTD) was 1.88 mg/kg iv q3w; dose limiting toxicity (DLT) was rash. At MTD (n=15), terminal phase half life (T½) of TA was 41 ± 25h and T½ of ADC was 29 ± 13h. Mean maximum plasma concentrations of free MMAE was 1.3–2.9% of TA concentration across all doses. Mean sGPNMB at baseline was 12 ng/ml (range 1.3–32 ng/ml), corresponding to 0.024 % of TA concentration at MTD. Anti-ADC Ab were detectible in 8/240 (3.3%) samples (n=54). Based on the T½, two additional dose schedules (qw and 2 out of 3w) were initiated (n=14). Pts received 0.75 mg/kg (n=3) and 1.0 mg/kg (n=5) in the qw schedule and 1.25 mg/kg (n=3) and 1.5 mg/kg (n=3) in 2 of 3w. The most common adverse events (AEs) were rash (n=6), pruritus (n=5) and fatigue (n=4). 1 DLT (Gr 3 rash) was observed at 1.0 mg/kg qw. Enrollment is ongoing in both schedules. Conclusions: The relatively short T½ of CR011-vcMMAE (∼40h) does not appear to be due to immunogenicity or sGPNMB-mediated clearance. Preliminary data suggest that weekly dosing is tolerated at higher per-cycle cumulative doses than the q3w schedule. [Table: see text]

Interaction of Metoprolol, Propranolol and Atenolol with Cimetidine

1982 ◽  
Vol 63 (s8) ◽  
pp. 451s-453s ◽  
Author(s):  
W. Kirch ◽  
H. Spahn ◽  
H. Köhler ◽  
E. Mutschler
Keyword(s):  
Plasma Concentration ◽  
Healthy Volunteers ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Concurrent Administration ◽  
Time Curve ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

1. Pharmacokinetics of metoprolol, propranolol and atenolol were investigated in six healthy volunteers after 7 days of oral monotherapy with these drugs and after 7 days concurrent administration, with each of these β-adrenoceptor antagonists with cimetidine. 2. Cimetidine did not interact with atenolol, whereas mean peak plasma concentrations of metoprolol were increased by 70%, and those of propranolol by 95% with concurrent administration of cimetidine (P < 0.05). 3. The area under the plasma concentration-time curve for propranolol and metoprolol was similarly increased (P < 0.05).

scholarly journals Pharmacokinetics of Buprenorphine and Sustained-release Buprenorphine in Common Marmosets (Callithrix jacchus)

2020 ◽  
Author(s):  
Casey B Fitz ◽  
Anna E Goodroe ◽  
David E Moody ◽  
Wenfang B Fang ◽  
Saverio V Capuano III
Keyword(s):  
Adverse Effects ◽  
Sustained Release ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Callithrix Jacchus ◽  
Terminal Phase ◽  
Pharmacokinetic Parameters ◽  
Common Marmosets ◽  
Adult Age ◽  
Concentration Time

Buprenorphine is an essential component of analgesic protocols in common marmosets (Callithrix jacchus). The use of buprenorphine HCl (BUP) and sustained-release buprenorphine (BSR) formulations has become commonplace in this species, but the pharmacokinetics have not been evaluated. Healthy adult (age, 2.4 to 6.8 y; 6 female and 6 male) common marmosets were enrolled in this study to determine the pharmacokinetic parameters, plasma concentration–time curves, and any apparent adverse effects of these compounds. Equal numbers of each sex were randomly assigned to receive BUP (0.02 mg/kg IM) orBSR (0.2 mg/kg SC), resulting in peak plasma concentrations (mean ± 1 SD) of 15.2 ± 8.1 and 2.8 ± 1.2 ng/mL, terminal phase t1/2 of 2.2 ± 1.0 and 32.6 ± 9.6 h, and AUC0-last of 16.1 ± 3.7 and 98.6 ± 42.7 ng×h/mL. The plasma concentrations of buprenorphine exceeded the proposed minimal therapeutic threshold (0.1 ng/mL) at 5 and 15 min after BUP and BSR administration,showing that both compounds are rapid-acting, and remained above that threshold through the final time points of 8 and 72h. Extrapolation of the terminal elimination phase of the mean concentration–time curves was used to develop the clinical dosing frequencies of 6 to 8 h for BUP and 3.0 to 3.5 d for BSR. Some adverse effects were observed after the administration of BUP to common marmosets in this study, thus mandating judicious use in clinical practice. BSR provided a safe, long-acting option for analgesia and therefore can be used to refine analgesic protocols in this species.

scholarly journals Pharmacokinetics and Pharmacodynamics of Fosfomycin and Its Activity against Extended-Spectrum-β-Lactamase-, Plasmid-Mediated AmpC-, and Carbapenemase-ProducingEscherichia coliin a Murine Urinary Tract Infection Model

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Ilya Nikolaevich Zykov ◽  
Ørjan Samuelsen ◽  
Lotte Jakobsen ◽  
Lars Småbrekke ◽  
Dan I. Andersson ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Clinical Strain ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Tract Infections

ABSTRACTFosfomycin has become an attractive treatment alternative for urinary tract infections (UTIs) due to increasing multidrug resistance (MDR) inEscherichia coli. In this study, we evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) indices of fosfomycin and itsin vivoactivity in an experimental murine model of ascending UTI. Subcutaneous administration of fosfomycin showed that the mean peak plasma concentrations of fosfomycin were 36, 280, and 750 mg/liter following administration of a single dose of 0.75, 7.5, and 30 mg/mouse, respectively, with an elimination half-life of 28 min, and urine peak concentrations of 1,100, 33,400, and 70,000 mg/liter expected to be sustained above 1 mg/liter (MIC of the test strain, NU14) for 5, 8, and 9.5 h, respectively. The optimal PK/PD indices for reducing urine colony counts (number of CFU per milliliter) were determined to be the area under the concentration-time curve/MIC from 0 to 72 h and the maximum concentration/MIC on the basis of the dose-dependent bloodstream PK and the results of an evaluation of six dosing regimens. With a dosing regimen of 15 mg/mouse twice (every 36 h), fosfomycin significantly reduced the number of CFU per milliliter of all susceptible strains in urine, including clinical MDR strains, except for one clinical strain (P= 0.062). Variable degrees of reduction were observed in the bladder and kidneys. No significant reductions in the number of CFU per milliliter were observed with the resistant strains. In conclusion, fosfomycin shows concentration-dependentin vivoactivity, and the results suggest that fosfomycin is an effective alternative to carbapenems in treating MDRE. coliin uncomplicated UTIs. The data on the effectiveness of fosfomycin against the MDR isolates along with the results of PK/PD modeling should facilitate the further development of improved recommendations for its clinical use.

scholarly journals Changes in the Pharmacokinetics of Phenytoin in Dextran Sulfate Sodium–Induced Ulcerative Colitis in Mice

2017 ◽  
Vol 36 (6) ◽  
pp. 485-491 ◽  
Author(s):  
Yoshiki Kusunoki ◽  
Yurika Kido ◽  
Yuichi Naito ◽  
Risako Kon ◽  
Nanaho Mizukami ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Protein Expression ◽  
Messenger Rna ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Plasma Concentrations ◽  
Control Group ◽  
Time Curve ◽  
Blood Concentrations ◽  
Expression Levels

We previously demonstrated that the expression levels of drug-metabolizing enzymes, cytochrome P450 (CYP) enzymes, in the liver are significantly decreased in a murine model of ulcerative colitis (UC). In this study, we investigated changes in the pharmacokinetics of phenytoin, a CYP2C substrate drug, in the presence of UC. Colitis was induced by feeding male mice 3.5% dextran sulfate sodium (DSS) dissolved in drinking water for 10 days. The messenger RNA (mRNA) expression of CYP2C29 and CYP2C37 and the protein expression of CYP2C in the liver were evaluated via real-time reverse transcription–polymerase chain reaction and Western blotting, respectively. In DSS-treated animals, both mRNA and protein expression levels of CYP2C in the liver were significantly reduced relative to those in control animals (by 20%-40%). Phenytoin (30 mg/kg) was administered orally in a single dose to mice, and plasma concentrations were measured. Plasma concentrations of phenytoin were higher in the DSS-treated group than in the control group at 12, 24, and 36 hours after administration. Animals given DSS also exhibited a higher area under the plasma concentration–time curve extrapolated to infinity (AUCinf, 315 μg·h/mL), a delayed elimination half-life ( T1/2, 8.1 hours), and a decreased body clearance (CL/F, 3.52 mL/h) compared with that of control animals (AUCinf, 215 μg·h/mL; T1/2, 3.6 h; CL/F, 5.58 mL/h). This study indicated that the presence of UC decreases CYP2C expression levels in the liver, thereby delaying the metabolism of CYP2C substrates, including phenytoin, and increasing blood concentrations of these substrates.

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