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1.
Int J Surg ; 79: 131-135, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32413504

ABSTRACT

BACKGROUND: The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. MATERIAL AND METHODS: To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 µg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. RESULTS: N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. CONCLUSION: This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Hepatectomy , Adult , Aged , Controlled Before-After Studies , Female , Humans , Male , Midazolam/blood , Middle Aged , Postoperative Period , Prospective Studies
2.
Br J Clin Pharmacol ; 84(8): 1738-1747, 2018 08.
Article in English | MEDLINE | ID: mdl-29618168

ABSTRACT

AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.


Subject(s)
Chlorzoxazone/pharmacokinetics , Cytochrome P-450 CYP2E1/metabolism , Obesity/metabolism , Administration, Oral , Adolescent , Area Under Curve , Body Mass Index , Child , Chlorzoxazone/administration & dosage , Diabetes Mellitus , Dose-Response Relationship, Drug , Fatty Liver , Female , Humans , Hydroxylation , Male , Metabolic Clearance Rate/physiology , Obesity/blood , Obesity/physiopathology , Obesity/urine
3.
Clin Pharmacol Ther ; 103(2): 341-348, 2018 02.
Article in English | MEDLINE | ID: mdl-28543042

ABSTRACT

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.


Subject(s)
Antiviral Agents/administration & dosage , Bile Acids and Salts/blood , Lipopeptides/administration & dosage , Reverse Transcriptase Inhibitors/pharmacokinetics , Tenofovir/pharmacokinetics , Administration, Oral , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Biomarkers/blood , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Female , Humans , Injections, Subcutaneous , Lipopeptides/adverse effects , Lipopeptides/pharmacokinetics , Male , Middle Aged , Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors , Organic Anion Transporters, Sodium-Dependent/metabolism , Prospective Studies , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/adverse effects , Risk Assessment , Symporters/antagonists & inhibitors , Symporters/metabolism , Tenofovir/administration & dosage , Tenofovir/adverse effects , Up-Regulation , Young Adult
5.
Schmerz ; 31(5): 516-523, 2017 10.
Article in German | MEDLINE | ID: mdl-28597312

ABSTRACT

BACKGROUND AND OBJECTIVES: The synthetic opioid tilidine is often used in chronic pain treatment. However, the activation via metabolism in patients with concomitant medication and reduced liver or kidney function is not thoroughly investigated. We therefore studied pain treatment efficacy, health-related quality of live and the metabolism of tilidine in patients with chronic pain. METHODS AND MATERIALS: In all, 48 patients, who were on a stable dose of oral prolonged release tilidine for at least 7 days, were included in this observational multicenter study. Liver and kidney function were assessed in routine blood samples, concentrations of tilidine, nortilidine and bisnortilidine were determined using a validated LC/MS/MS method. Comedication was registered and patients experience with regard to quality of life, pain, gastrointestinal symptoms and adverse events was assessed in standardised questionnaires. RESULTS: On average a daily dose of 180 mg tilidine was taken. Dose normalized plasma concentrations of the active metabolite nortilidine ranged between 1.6 ng/ml and 76.5 ng/ml (mean 29.2 ± 25.1 ng/ml). Ratios between tilidine and nortilidine were on average 0.28 (median = 0.13, standard deviation = 0.67). Patients were on 1 to 14 different concomitant medications. About 66% of the patients had sufficient pain treatment. Almost no opioid-induced constipation was observed. Only few patients had decreased kidney or liver function which did not result in elevated nortilidine concentrations. CONCLUSION: Pain treatment using tilidine resulted in variable nortilidine concentrations which are obviously not strongly influenced by comedication or reduced liver or kidney function. Only a few side effects were observed with almost no opioid-induced constipation.


Subject(s)
Chronic Pain/drug therapy , Quality of Life/psychology , Tilidine/analogs & derivatives , Tilidine/pharmacokinetics , Tilidine/therapeutic use , Adult , Aged , Aged, 80 and over , Chronic Pain/psychology , Delayed-Action Preparations , Drug Interactions , Drug Therapy, Combination , Female , Humans , Kidney Function Tests , Liver Function Tests , Male , Middle Aged
6.
Cell Death Dis ; 6: e1657, 2015 Feb 19.
Article in English | MEDLINE | ID: mdl-25695609

ABSTRACT

For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.


Subject(s)
Histone Deacetylases/metabolism , Neuroblastoma/metabolism , Repressor Proteins/metabolism , Tretinoin/pharmacology , Animals , Blotting, Western , Cell Line, Tumor , Cell Survival/drug effects , Female , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/genetics , Humans , Hydroxamic Acids , Indoles/pharmacology , Mice , Mice, Nude , Repressor Proteins/genetics , Xenograft Model Antitumor Assays
7.
J Antimicrob Chemother ; 69(12): 3311-9, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25096076

ABSTRACT

OBJECTIVES: To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz. PATIENTS AND METHODS: Two study arms (arm 1, n = 41 and arm 2, n = 21) were recruited into this study. In arm 1, cholesterol and 4ß-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4ß-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed. RESULTS: A one-compartment, enzyme turnover model described 4ß-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error = 15%), 3.3 (relative standard error = 33.1%) and 4.0 (relative standard error = 37.1%) average fold induction of CYP3A for extensive (CYP2B6*1/*1), intermediate (CYP2B6*1/*6) and slow (CYP2B6*6/*6) efavirenz metabolizers, respectively. The rate constant of 4ß-hydroxycholesterol formation [mean (95% CI)] just before completion of TB treatment [efavirenz/rifampicin co-treatment, 7.40 × 10(-7) h(-1) (5.5 × 10(-7)-1.0 × 10(-6))] was significantly higher than that calculated 8 weeks after completion [efavirenz alone, 4.50 × 10(-7) h(-1) (4.40 × 10(-7)-4.52 × 10(-7))]. The CYP3A induction dropped to 62% of its maximum by week 8 of completion. CONCLUSIONS: Our results indicate that efavirenz induction of CYP3A is influenced by CYP2B6 genetic polymorphisms and that efavirenz/rifampicin co-treatment results in higher induction than efavirenz alone.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Antitubercular Agents/pharmacokinetics , Benzoxazines/pharmacokinetics , Cytochrome P-450 CYP2B6/genetics , Cytochrome P-450 CYP3A/metabolism , Hydroxycholesterols/analysis , Rifampin/pharmacokinetics , Adult , Alkynes , Anti-HIV Agents/therapeutic use , Antitubercular Agents/therapeutic use , Benzoxazines/therapeutic use , Cyclopropanes , Female , Genotype , HIV Infections/drug therapy , Humans , Male , Middle Aged , Rifampin/therapeutic use , Tuberculosis/drug therapy
9.
Clin Pharmacol Ther ; 93(6): 564-71, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23511711

ABSTRACT

The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001-3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and C(max) increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000-fold concentration range, and therefore that nano- and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.


Subject(s)
Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Ketoconazole/pharmacology , Midazolam/administration & dosage , Midazolam/pharmacology , Adolescent , Adult , Alleles , Area Under Curve , Cytochrome P-450 CYP3A Inhibitors , Dose-Response Relationship, Drug , Drug Interactions/genetics , Female , Genotype , Humans , Ketoconazole/administration & dosage , Male , Midazolam/pharmacokinetics , Middle Aged , Sex Characteristics
10.
Pharmacogenomics J ; 13(6): 484-9, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23089673

ABSTRACT

We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4ß-hydroxycholesterol/cholesterol (4ß-OHC/Chol) as a marker for CYP3A induction. Plasma 4ß-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4ß-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4ß-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4ß-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.


Subject(s)
Benzoxazines/therapeutic use , Cytochrome P-450 CYP3A/biosynthesis , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/therapeutic use , Alkynes , Cyclopropanes , Cytochrome P-450 CYP3A/genetics , Enzyme Induction , Female , HIV Infections/enzymology , Humans , Male , Prospective Studies
11.
Pharmacogenomics J ; 12(6): 499-506, 2012 Dec.
Article in English | MEDLINE | ID: mdl-21862974

ABSTRACT

The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.


Subject(s)
Antiretroviral Therapy, Highly Active/adverse effects , Aryl Hydrocarbon Hydroxylases/genetics , Benzoxazines/adverse effects , Chemical and Drug Induced Liver Injury/genetics , HIV Infections/drug therapy , Oxidoreductases, N-Demethylating/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Adult , Alkynes , Benzoxazines/blood , Cohort Studies , Cyclopropanes , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP3A/genetics , Female , Genotype , Humans , Male , Proportional Hazards Models , Prospective Studies
12.
Clin Pharmacol Ther ; 90(5): 666-73, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21937987

ABSTRACT

We established a new limited sampling strategy to assess CYP3A activity and evaluated the time course of reversible (voriconazole) and irreversible (ritonavir) CYP3A inhibition. In this randomized trial, two groups, each with eight healthy participants, received CYP3A inhibitors voriconazole or ritonavir orally for 9 days, with 3 mg midazolam (MDZ) administered before the inhibitor treatment, on days 1, 2, 3, 5, 8, and 9 during inhibitor treatment, and on days 10, 11, and 12 (3 days) after discontinuation. Plasma MDZ area under the curve (AUC) between 2 and 4 h after oral administration in the form of a solution strongly correlated with MDZ clearance. Using this parameter, maximum inhibition of voriconazole and ritonavir was calculated to have occurred only 48 h after starting of the inhibitor (percentage of baseline MDZ clearance, voriconazole: 10.6%; ritonavir: 8.4%). Recovery of CYP3A activity occurred with a half-life of 24 h after voriconazole, whereas ritonavir inhibition was still strong 3 days after discontinuation. These findings underscore the substantial and gradual alterations in dose requirements in the first days of and after such combination therapies.


Subject(s)
Cytochrome P-450 CYP3A Inhibitors , Enzyme Inhibitors/pharmacology , Pyrimidines/pharmacology , Ritonavir/pharmacology , Triazoles/pharmacology , Administration, Oral , Adolescent , Adult , Area Under Curve , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Female , Half-Life , Humans , Male , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Middle Aged , Time Factors , Voriconazole , Young Adult
13.
Clin Pharmacol Ther ; 90(3): 406-13, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21814190

ABSTRACT

We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long-term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8-hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8-hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8-hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*1/*1 genotypes. Ours is the first report of the CYP2B6 genotype-dependent effect of RIF on long-term EFV autoinduction.


Subject(s)
Antibiotics, Antitubercular/therapeutic use , Aryl Hydrocarbon Hydroxylases/genetics , Benzoxazines/blood , Oxidoreductases, N-Demethylating/genetics , Reverse Transcriptase Inhibitors/blood , Rifampin/therapeutic use , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Alkynes , Alleles , Anti-HIV Agents/blood , Anti-HIV Agents/metabolism , Anti-HIV Agents/therapeutic use , Antibiotics, Antitubercular/blood , Antiretroviral Therapy, Highly Active , Benzoxazines/metabolism , Benzoxazines/therapeutic use , Cyclopropanes , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP3A/genetics , Drug Interactions , Enzyme Induction , Female , Genotype , HIV Infections/drug therapy , HIV Infections/genetics , HIV-1/drug effects , HIV-1/genetics , Humans , Male , Polymorphism, Single Nucleotide , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/therapeutic use , Rifampin/blood , Tuberculosis/drug therapy , Tuberculosis/genetics
14.
Clin Pharmacol Ther ; 88(5): 676-84, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20881953

ABSTRACT

We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure continues up to week 16 and predominantly affects CYP2B6 extensive metabolizers. Among CYP2B6 slow metabolizers, the presence of a CYP3A5 genotype allele is associated with greater effects of efavirenz autoinduction on plasma concentrations of the drug. The cumulative induction may influence the long-term antiretroviral therapy outcome, particularly in CYP2B6*1 carriers.


Subject(s)
Benzoxazines/pharmacokinetics , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Alkynes , Antiretroviral Therapy, Highly Active , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Benzoxazines/administration & dosage , Benzoxazines/blood , Biotransformation , Cyclopropanes , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Drug Administration Schedule , Female , Genotype , HIV Infections/blood , Humans , Hydroxylation , Male , Middle Aged , Oxidoreductases, N-Demethylating/genetics , Oxidoreductases, N-Demethylating/metabolism , Phenotype , Prospective Studies , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/blood , Sex Factors , Tanzania
15.
Clin Pharmacol Ther ; 87(2): 191-6, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19924124

ABSTRACT

We aimed to assess the effect of coadministration and withdrawal of a potent cytochrome P450 3A (CYP3A) inhibitor (ritonavir) and a potent CYP3A inducer (St John's wort) on CYP3A enzyme activity in an open, fixed-sequence study design. We investigated the pharmacokinetics of midazolam: (i) at baseline, (ii) after a single dose of either St John's wort or ritonavir (each n = 6), (iii) after 14 days of coadministration of ritonavir (300 mg b.i.d.) and St John's wort (300 mg t.i.d.), and (iv) at 2 days after cessation of both St John's wort and ritonavir. Combined administration of inducer and inhibitor resulted in a predominance of enzyme inhibition: coadministration of St John's wort and ritonavir with intravenous administration of midazolam resulted in an increase in the area under the plasma concentration-time curve (AUC)(0-8 h) of midazolam to 180% of baseline value, whereas with orally administered midazolam, the AUC(0-6 h) increased to 412% of baseline value (P < 0.05 for each). After cessation of the coadministered drugs, the AUC(0-6 h) of orally administered midazolam decreased to 6% of the level observed during combined administration, and the AUC(0-8 h) of intravenously administered midazolam decreased to 33% of the values observed during combined administration (P < 0.001 for each). Induction may be unmasked after the withdrawal of a combination of a potent CYP3A inhibitor and a potent CYP3A inducer, leading to substantial drops in drug exposure of CYP3A substrates. This may require substantial dose adjustments, particularly of orally administered drugs.


Subject(s)
Cytochrome P-450 CYP3A/drug effects , Hypericum/chemistry , Midazolam/pharmacokinetics , Plant Extracts/pharmacology , Ritonavir/pharmacology , Administration, Oral , Adult , Area Under Curve , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Enzyme Induction/drug effects , Enzyme Inhibitors/pharmacology , Female , HIV Protease Inhibitors/pharmacology , Humans , Infusions, Intravenous , Male , Midazolam/administration & dosage , Substance Withdrawal Syndrome , Young Adult
16.
Int J Clin Pharmacol Ther ; 45(8): 431-7, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17725176

ABSTRACT

OBJECTIVE: Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. METHODS: In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. RESULTS: Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean +/- SD 190 +/- 42 versus 290 +/- 83 ml min(-1), 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. CONCLUSIONS: 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.


Subject(s)
Caffeine/pharmacokinetics , Central Nervous System Stimulants/pharmacokinetics , Kidney/metabolism , Probenecid/pharmacology , Renal Agents/pharmacology , Xanthines/metabolism , Adult , Area Under Curve , Arylamine N-Acetyltransferase/metabolism , Chromatography, High Pressure Liquid , Creatinine/blood , Creatinine/urine , Cross-Over Studies , Cytochrome P-450 CYP1A2/metabolism , Depression, Chemical , Double-Blind Method , Female , Humans , Male , Spectrophotometry, Ultraviolet , Xanthine Oxidase/metabolism
17.
Clin Pharmacol Ther ; 81(5): 708-12, 2007 May.
Article in English | MEDLINE | ID: mdl-17329995

ABSTRACT

CYP3A is the main enzyme subfamily involved in the metabolism of the HIV protease-inhibitor saquinavir. We hypothesized that individuals homozygous for CYP3A5*1 might have a higher oral clearance of saquinavir, compared with subjects lacking functional CYP3A5 alleles. A single-dose pharmacokinetic trial of saquinavir soft gel capsules, 1,200 mg, was performed in 16 black Tanzanian healthy volunteers with two functional CYP3A5 alleles (*1/*1) and in 18 volunteers without functional CYP3A5 alleles (both alleles being either *3, *6, or *7). The median area under the plasma concentration-time curve (AUC)0-24 reached among subjects with two functional alleles was 1,410 ng h/ml (interquartile range (IQR) 826-1,929), whereas it was 2,138 ng h/ml (IQR 1,380-3,331) in subjects without (P=0.0533, Mann-Whitney U-test). The median ratio of saquinavir over its M2 plus M3 hydroxy metabolites in urine was 64 (IQR 52-73) in subjects with two functional alleles, whereas it was 145 (IQR 89-181) in those without (P=0.000078, Mann-Whitney U-test). In conclusion, saquinavir is metabolized by CYP3A5. The median AUC0-24 for saquinavir among individuals with two functional CYP3A5 alleles was 34% lower than among those with no functional alleles. To clarify the clinical importance of the CYP3A5 polymorphism, further studies should be conducted on saquinavir, dosed to steady state, in the presence of ritonavir boosting.


Subject(s)
Cytochrome P-450 Enzyme System/genetics , HIV Protease Inhibitors/metabolism , Saquinavir/metabolism , Adult , Alleles , Area Under Curve , Capsules , Cytochrome P-450 CYP3A , Endpoint Determination , Female , Humans , Hydroxylation , Male , Middle Aged , Polymorphism, Genetic/genetics , Reverse Transcriptase Polymerase Chain Reaction
18.
Pediatr Blood Cancer ; 49(2): 203-7, 2007 Aug.
Article in English | MEDLINE | ID: mdl-16333861

ABSTRACT

Invasive aspergillosis is an increasing problem in immuno-incompetent patients after prolonged steroid therapy, cancer radio-chemotherapy, and bone marrow or solid organ transplantation. Cerebral aspergillosis is a well-described complication of the invasive aspergillosis but only in rare cases, the brain is the sole site of infection. Despite increasing availability of antifungal drugs, the prognosis of cerebral aspergillosis is poor. We report on an 11-year-old boy with medulloblastoma in the area of the fourth ventricle. Following tumor surgery and radio-chemotherapy, several abscess-like structures occurred in the operating field. After incomplete abscess, resection histology and culture confirmed a localized Aspergillus fumigatus infection. The initial treatment of the Aspergillus fumigatus infection with conventional amphotericin B failed, and treatment with the triazole voriconazole was started. Intravenous treatment with voriconazole resulted in a reduction of the Aspergillus fumigatus abscess. After switching to oral ambulatory therapy, the Aspergillus fumigatus abscess increased in size. To improve treatment, voriconazole dosage was adapted to reach drug concentrations in cerebrospinal fluid (CSF) above the minimal fungicidal concentration and plasma specimens. During the concentration-controlled voriconazole therapy for a period of 18 months, a complete response was achieved.


Subject(s)
Antifungal Agents/therapeutic use , Aspergillus fumigatus , Brain Abscess/drug therapy , Cerebral Ventricle Neoplasms/complications , Medulloblastoma/complications , Neuroaspergillosis/drug therapy , Pyrimidines/therapeutic use , Surgical Wound Infection/drug therapy , Triazoles/therapeutic use , Administration, Oral , Antifungal Agents/administration & dosage , Antifungal Agents/cerebrospinal fluid , Antifungal Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Aspergillus fumigatus/drug effects , Brain Abscess/diagnosis , Brain Abscess/etiology , Brain Abscess/microbiology , Carboplatin/administration & dosage , Cerebral Ventricle Neoplasms/drug therapy , Cerebral Ventricle Neoplasms/radiotherapy , Cerebral Ventricle Neoplasms/surgery , Child , Combined Modality Therapy , Cranial Irradiation , Craniotomy , Cyclophosphamide/administration & dosage , Diagnostic Errors , Etoposide/administration & dosage , Humans , Immunocompromised Host , Infusions, Intravenous , Lomustine/administration & dosage , Male , Medulloblastoma/drug therapy , Medulloblastoma/radiotherapy , Medulloblastoma/surgery , Methotrexate/administration & dosage , Neoplasm Recurrence, Local/diagnosis , Neuroaspergillosis/complications , Neuroaspergillosis/diagnosis , Pyrimidines/administration & dosage , Pyrimidines/cerebrospinal fluid , Pyrimidines/pharmacology , Surgical Wound Infection/etiology , Triazoles/administration & dosage , Triazoles/cerebrospinal fluid , Triazoles/pharmacology , Vincristine/administration & dosage , Voriconazole
19.
Clin Infect Dis ; 39(6): e49-52, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15472801

ABSTRACT

A 15-year-old patient with acute lymphoblastic leukemia and Fusarium infection was treated with voriconazole. She developed asymptomatic bradycardia, QT interval prolongation, and nonsustained, polymorphic ventricular tachycardia, which recurred upon rechallenge with the drug. Voriconazole levels and metabolism were within expected normal values. This non-concentration-dependent, voriconazole-associated ventricular tachycardia mandates cardiac rhythm monitoring during voriconazole treatment.


Subject(s)
Antifungal Agents/adverse effects , Bradycardia/chemically induced , Pyrimidines/adverse effects , Tachycardia, Ventricular/chemically induced , Triazoles/adverse effects , Adolescent , Female , Fusarium , Humans , Mycoses/drug therapy , Opportunistic Infections/drug therapy , Torsades de Pointes/chemically induced , Voriconazole
20.
Clin Pharmacol Ther ; 70(5): 405-14, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11719726

ABSTRACT

BACKGROUND: The antidiarrheal drug loperamide is frequently used to treat ritonavir-associated diarrhea in patients with human immunodeficiency virus. The absence of marked central opioid effects has been attributed to its low bioavailability and its poor penetration of the blood-brain barrier, both of which might be altered by ritonavir, a potent P-glycoprotein and cytochrome P4503A inhibitor. METHODS: A 16-mg dose of loperamide was administered to 12 healthy male and female volunteers together with either 600 mg of ritonavir or placebo. Detailed pharmacokinetics of loperamide and its metabolites were determined over 72 hours. Central opioid effects were measured by evaluation of pupil diameter, cold pressor test, and transcutaneous PCO2 and PO2. RESULTS: Ritonavir caused a major pharmacokinetic interaction, increasing the area under the concentration-time curve of loperamide from 104 +/- 60 h x pmol/ml after placebo to 276 +/- 68 h. pmol/ml and delayed formation of the major metabolite desmethylloperamide (time to reach maximum concentration after drug administration [t(max)], 7.1 +/- 2.6 hours versus 19.6 +/- 9.1 hours). The urinary metabolic ratio of loperamide increased 3 times whereas the total molar amount of loperamide and metabolites excreted in urine remained unchanged. No central pharmacodynamic effects were observed after coadministration of loperamide with either ritonavir or placebo. CONCLUSION: This study demonstrates a major metabolic interaction probably by cytochrome P4503A4 with no evidence of P-glycoprotein involvement. This might explain the lack of central effects after ritonavir.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Antidiarrheals/blood , Aryl Hydrocarbon Hydroxylases , HIV Protease Inhibitors/pharmacology , Loperamide/blood , Ritonavir/pharmacology , Adult , Area Under Curve , Cross-Over Studies , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/physiology , Double-Blind Method , Female , Humans , Male , Middle Aged , Oxidoreductases, N-Demethylating/antagonists & inhibitors , Oxidoreductases, N-Demethylating/physiology
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