Avvisi di avvertenza
Estensione di tempo QT
Effetti avversi del farmaco
|Mal di testa|
Varianti ✨Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.
Aree di applicazione
Spiegazioni per i pazienti
Avvisi di avvertenza
La somministrazione di fenitoina e itraconazolo deve essere evitata.
Sono possibili una diminuzione dell'itraconazolo e un aumento delle concentrazioni di fenitoinaMeccanismo: l' itraconazolo è un substrato e un inibitore del CYP3A4, la fenitoina è tra l'altro induttore del CYP3A4. Questo può portare a mutue influenze farmacocinetiche.
Effetto: ci si può aspettare che le concentrazioni di itraconazolo siano significativamente ridotte e che la terapia possa persino fallire. Negli studi di interazione del produttore, la biodisponibilità di itraconazolo o idrossi-itraconazolo in combinazione con fenitoina e altri potenti induttori enzimatici è stata ridotta del 60-90%. Inoltre, sono possibili maggiori concentrazioni di fenitoina.
Misure: l'associazione deve essere evitata poiché la terapia con itraconazolo potrebbe non riuscire. Anche il produttore (itraconazolo) sconsiglia la combinazione. Si deve prendere in considerazione un anticonvulsivante alternativo (a seconda dell'indicazione per la fenitoina, gabapentin potrebbe essere un'opzione) o un antifungino.
|Fenitoina||1.11 [1.11,1.94] 1||1||1.11|
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. Non abbiamo rilevato alcun cambiamento nell'esposizione alla ciprofloxacina. Attualmente non è possibile stimare l'influenza di itraconazolo e fenitoina. L'esposizione alla fenitoina aumenta al 111%, se combinato con ciprofloxacina (100%) e itraconazolo (111%). L'AUC è compresa tra 111% e 194% a seconda del
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La ciprofloxacina ha una biodisponibilità orale media [ F ] del 70%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 3.5 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è molto debole al 30%. Circa il 55.0% di una dose somministrata viene escreta immodificata attraverso i reni e questa proporzione è raramente modificata dalle interazioni. Il metabolismo avviene principalmente tramite CYP1A2 e il trasporto attivo avviene in parte tramite BCRP, OATP1A2 e PGP.
La itraconazolo ha una biodisponibilità orale media [ F ] del 55%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è di 21 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 84 ore. Il legame proteico [ Pb ] è molto forte al 99.8% e il volume di distribuzione [ Vd ] è molto grande a 796 litri, ecco perché, con una velocità di estrazione epatica media di 0,9, sono rilevanti sia il flusso sanguigno epatico [Q] che una variazione del legame proteico [Pb]. Il metabolismo avviene principalmente tramite CYP3A4 e il trasporto attivo avviene in particolare tramite PGP.
La fenitoina ha un'elevata biodisponibilità orale [ F ] del 85%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è di 13 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 52 ore. Il legame proteico [ Pb ] è moderatamente forte al 90% e il volume di distribuzione [ Vd ] è di 47 litri nell'intervallo medio, Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene tramite CYP2C19, CYP2C9 e CYP2E1, tra gli altri e il trasporto attivo avviene in particolare tramite PGP.
|Effetti serotoninergici a||0||Ø||Ø||Ø|
Valutazione: Secondo le nostre conoscenze, né la ciprofloxacina, itraconazolo né la fenitoina aumentano l'attività serotoninergica.
|Kiesel & Durán b||0||Ø||Ø||Ø|
Valutazione: Secondo i nostri risultati, né la ciprofloxacina né la itraconazolo aumentano l'attività anticolinergica. L'effetto anticolinergico della fenitoina non è rilevante.
Estensione di tempo QT
Valutazione: In combinazione, ciprofloxacina e itraconazolo possono potenzialmente innescare aritmie ventricolari di tipo torsione di punta. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la fenitoina.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||cip||itr||fen|
|Mal di testa||8.9 %||3.0||6.1↓||n.a.|
|Infezione delle vie respiratorie superiori||8.0 %||n.a.||8.0↓||n.a.|
|Eruzione cutanea||7.7 %||1.8||6.0↓||n.a.|
|Edema periferico||4.0 %||n.a.||4.0↓||n.a.|
Diarrea (3.8%): itraconazolo, ciprofloxacina
Dolore addominale (2.9%): itraconazolo
Pancreatite: itraconazolo, ciprofloxacina
Diarrea da Clostridium difficile: ciprofloxacina
Emorragia gastrointestinale: ciprofloxacina
Ipertrofia gengivale: fenitoina
Vertigini (3.6%): itraconazolo, fenitoina
Compromissione della memoria: ciprofloxacina, fenitoina
Disturbo dell'attenzione: ciprofloxacina
Sindrome di Guillain-Barré: ciprofloxacina
Neuropatia periferica: ciprofloxacina
Pseudotumor cerebri: ciprofloxacina
Aumento della pressione intracranica: ciprofloxacina
Ipertensione (3%): itraconazolo
Infarto miocardico: ciprofloxacina
Insufficienza cardiaca: itraconazolo
Secrezione nasale (3%): ciprofloxacina
Edema polmonare: itraconazolo
Febbre (2.5%): itraconazolo
Fatica (2.3%): itraconazolo
Epatotossicità: itraconazolo, ciprofloxacina
Insufficienza epatica: ciprofloxacina
Reazione di ipersensibilità: itraconazolo, ciprofloxacina
Sindrome DRESS: fenitoina
Necrolisi epidermica tossica: ciprofloxacina, fenitoina
Sindrome di Stevens Johnson: ciprofloxacina, fenitoina
Dermatosi bollosa: fenitoina
Cistite emorragica: ciprofloxacina
Insufficienza renale: ciprofloxacina
Nefrite tubulointerstiziale: ciprofloxacina
Leucopenia: ciprofloxacina, fenitoina
Agranulocitosi: ciprofloxacina, fenitoina
Anemia aplastica: ciprofloxacina
Anemia emolitica: ciprofloxacina
Trombocitopenia: ciprofloxacina, fenitoina
Perdita dell'udito: itraconazolo
Miastenia grave: ciprofloxacina
Rottura del tendine: ciprofloxacina
Aneurisma aortico: ciprofloxacina
Sulla base delle vostre
Abstract: Phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt. Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in Scandinavia. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins. Clinically important displacement can be caused by bilirubin and several drugs, particularly sodium valproate, which is often combined with phenytoin. Displacement will lower the total serum concentration but will little affect the free drug concentration. The metabolism of phenytoin to the major metabolite, 5-(p-hydroxyphenyl)-5-(phenylhydantoin, is saturable, giving rise to a non linear dose-serum concentration relationship. Therefore, the dose range compatible with a therapeutic serum concentration is narrow within subjects, and monitoring serum concentrations is of particular value in dosage tailoring. In renal failure, the binding of phenytoin to plasma proteins is reduced and therefore a lower range of serum drug concentrations is compatible with therapeutic control. In liver disease, binding may also be impaired but delayed metabolism may occur in addition. During pregnancy the serum concentration may fall progressively as pregnancy advances, probably due to an increased rate of metabolism. Phenytoin readily crosses the placenta, and is metabolised rapidly by the neonate exposed in utero.
Abstract: Twelve patients receiving therapy with an azole agent (ketoconazole, itraconazole, and/or fluconazole) for systemic mycoses experienced drug interactions with rifampin, phenytoin, and/or carbamazepine resulting in substantial decreases in azole concentrations in serum. All four patients receiving azoles and concurrent phenytoin and/or carbamazepine failed to respond to treatment or suffered a relapse of their fungal infection. Four of five patients with cryptococcosis who received itraconazole and rifampin responded despite decreases in their serum itraconazole concentrations; synergy between itraconazole and rifampin was documented by in vitro analysis of inhibition and of killing of Cryptococcus neoformans isolates from all patients receiving this combination. In contrast, two patients with coccidioidomycosis failed to respond to itraconazole/rifampin. Moreover, two patients with cryptococcosis suffered a relapse or persistence of seborrheic dermatitis while receiving itraconazole/rifampin. The latter combination showed synergy in vitro in the inhibition of the mycelial phase of Coccidioides immitis and, to a lesser extent, of the pathogenic spherule phase of this fungus; synergy in the killing of C. immitis was not noted, nor was synergy seen against Malassezia furfur, the purported etiologic agent of seborrheic dermatitis. These findings illustrate several drug interactions that may affect clinical outcome and that must be considered in the management of antifungal therapy.
Abstract: 1. In a double-blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin.
Abstract: Clearance of phenytoin after i.v. injection of 100 mg was studied in six patients before and after 2 weeks daily treatment with 450 mg rifampicin, and in 14 patients with tuberculosis receiving standard treatment with 450 mg rifampicin, 300 mg isoniazid, and 1200 mg ethambutol daily. Acetylator status was measured by urinary acetylated sulphadimidine. Clearance of phenytoin in patients receiving only rifampicin increased from 46.7 ml min-1 +/- 20.6 ml min-1 to 97.8 ml min-1 +/- 33.4 ml min-1 (P less than 0.01), while clearance in patients on three drugs increased from 47.1 +/- 23.4 ml min-1 to 81.3 ml min-1 +/- 41.6 ml min-1 (P less than 0.01). No significant differences were observed between the six fast acetylators and the eight slow acetylators. Phenytoin kinetics were unchanged after further 3 months of combined treatment. Rifampicin is a strong inducer of the elimination of phenytoin. Combined treatment with isoniazid has no counter-acting effect in either fast or slow acetylators.
Abstract: No Abstract available
Abstract: No Abstract available
Abstract: OBJECTIVE: To study the disposition of single doses of phenytoin and itraconazole when administered alone and after chronic treatment with the other drug. METHODS: Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were given a single 300 mg oral dose of phenytoin before and after 15 days of itraconazole (200 mg once daily). Blood was collected for 96 hours after each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay. RESULTS: Phenytoin decreased the area under the concentration-time curve (AUC) of itraconazole by more than 90%, from 3203 to 224 ng.hr/ml, accompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng.hr/ml) and half-life (11.3 versus 2.9 hours). Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in any other pharmacokinetic parameter. CONCLUSIONS: The striking decrease in itraconazole concentrations with phenytoin is due to induction of metabolism combined with a reduction in the degree of saturable metabolism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in patients with fungal infections who are receiving both itraconazole and phenytoin.
Abstract: The pharmacokinetics of intravenous ciprofloxacin and its metabolites were characterized in 42 subjects with various degrees of renal function (group 1, Clcr (mL/min/1.73 m2) > 90, n = 10; group 2, Clcr 61-90, n = 11; group 3, Clcr 31-60, n = 11; group 4, Clcr < or = 30, n = 10). The dosage regimens were-groups 1 and 2: 400 mg i.v. at 8 hourly intervals; group 3: 400 mg i.v. at 12 hourly intervals and group 4: 300 mg i.v. at 12 hourly intervals. Subjects received a single dose on days 1 and 5 and multiple doses on days 2-4. Multiple plasma and urine samples were collected on days 1 and 5 for the analysis of ciprofloxacin and its metabolites (M1, M2 and M3). Plasma concentrations (Cmax and AUC) of ciprofloxacin and its M1 and M2 metabolites were significantly increased in subjects with reduced Clcr values (Clcr < 60 mL/min/1.73 m2) compared with normal subjects (Clcr > 90 mL/min/1.73 m2). A positive correlation was observed between ciprofloxacin clearance (Cl) and Clcr with a slope of 0.29 (r2 = 0.78) and between renal clearance (Clr) and Clcr with a slope of 0.19 (r2 = 0.84). For patients with severe infections a dosage regimen of 400 mg iv 8 hourly is appropriate in patients with Clcr > 60 mL/min/1.73 m2. In patients with Clcr values of 31-60 mL/min/1.73 m2 a dosage regimen of 400 mg 12 hourly provides similar plasma concentrations to those observed for subjects with Clcr 61-90 mL/min/1.73 m2 receiving 400 mg 8 hourly. Based on modeling of the plasma concentrations in subjects with Clcr < or = 30 ml/min/1.73 m2, a dosage regimen of 400 mg every 24 h will provide plasma concentrations similar to those observed in subjects with Clcr between 61-90 mL/min/1.73 m2 given 400 mg every 8 h.
Abstract: STUDY OBJECTIVE: To compare the rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin administration. DESIGN: Retrospective database analysis. INTERVENTION: Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. MEASUREMENTS AND MAIN RESULTS: In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. Ciprofloxacin was associated with a significantly lower rate of torsades de pointes (0.3 cases/10 million prescriptions, 95% confidence interval [CI] 0.0-1.1) than levofloxacin (5.4/10 million, 95% CI 2.9-9.3, p<0.001) or gatifloxacin (27/10 million, 95% CI 12-53, p<0.001 for comparison with ciprofloxacin or levofloxacin). When the analysis was limited to the first 16 months after initial U.S. approval of the agent, the rates for levofloxacin (16/10 million) and gatifloxacin (27/10 million) were similar (p>0.5). CONCLUSION: Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Abstract: Ciprofloxacin has been widely used for treating infections and has been found to have very low cardiovascular side effects. QTc prolongation with the use of ciprofloxacin is yet to be reported in literature. A case report highlighting QTc prolongation by use of ciprofloxacin is being presented.
Abstract: Itraconazole (ITZ) is a potent inhibitor of CYP3A in vivo. However, unbound plasma concentrations of ITZ are much lower than its reported in vitro Ki, and no clinically significant interactions would be expected based on a reversible mechanism of inhibition. The purpose of this study was to evaluate the reasons for the in vitro-in vivo discrepancy. The metabolism of ITZ by CYP3A4 was studied. Three metabolites were detected: hydroxy-itraconazole (OH-ITZ), a known in vivo metabolite of ITZ, and two new metabolites: keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). OHITZ and keto-ITZ were also substrates of CYP3A4. Using a substrate depletion kinetic approach for parameter determination, ITZ exhibited an unbound K(m) of 3.9 nM and an intrinsic clearance (CLint) of 69.3 ml.min(-1).nmol CYP3A4(-1). The respective unbound Km values for OH-ITZ and keto-ITZ were 27 nM and 1.4 nM and the CLint values were 19.8 and 62.5 ml.min(-1).nmol CYP3A4(-1). Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction. Both ITZ and OH-ITZ were competitive inhibitors of CYP3A4, with unbound Ki (1.3 nM for ITZ and 14.4 nM for OH-ITZ) close to their respective Km. ITZ, OH-ITZ, keto-ITZ and ND-ITZ exhibited unbound IC50 values of 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively, when coincubated with human liver microsomes and midazolam (substrate concentration < Km). These findings demonstrate that ITZ metabolites are as potent as or more potent CYP3A4 inhibitors than ITZ itself, and thus may contribute to the inhibition of CYP3A4 observed in vivo after ITZ dosing.
Abstract: The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
Abstract: Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
Abstract: OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This randomized, open-label, parallel-group, multiple-dose study was conducted in healthy adult volunteers to assess the potential for a drug interaction between phenytoin and the posaconazole tablet formulation. METHODS: Subjects were randomly assigned for 10 days to one of the following treatments: posaconazole (200 mg once daily), phenytoin (200 mg once daily), or posaconazole (200 mg once daily) and phenytoin (200 mg once daily). Blood samples were collected on days 1 and 10 for pharmacokinetic evaluation of posaconazole and phenytoin concentrations. RESULTS: A total of 36 healthy men enrolled in the study. On day 1, the maximum plasma concentration (C(max)) and area under the concentration-time curve calculated from time 0-24 h post-dose (AUC(0-24)) were unchanged upon co-administration. At steady state (day 10), co-administration of posaconazole with phenytoin resulted in 44% (p = 0.012) and 52% (p = 0.007) decreases in posaconazole C(max) and AUC(0-24), respectively. These decreases in exposure corresponded with a 90% increase in steady-state clearance of orally administered posaconazole. Phenytoin C(max) and AUC(0-24) were not significantly altered upon co-administration of the two agents, 24% increase in C(max) (p = 0.196) and 25% increase in AUC(0-24) (p = 0.212) values, although inter-subject variability was observed within this group. CONCLUSION: Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin levels in some subjects, concomitant use of these agents should be avoided unless the benefit outweighs the risk.
Abstract: PURPOSE: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable. METHOD: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration. RESULTS: The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods. CONCLUSION: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.
Abstract: AIMS: To assess the role of MDR1 and gamma-aminobutyric acid receptor-gamma 2 sub unit (GABRG2) gene polymorphism in seizure susceptibility in generalized seizure (GS) and febrile seizure (FS) patients and to evaluate MDR1 C3435T gene polymorphism's role in absorption of the anti-epileptic drug, phenytoin (PHT) in a cohort of patients. METHODS: One hundred twenty-seven cases of seizure (86 GS and 41 FS) patients were analyzed for MDR1 C3435T and GABRG2 C588T gene polymorphisms using restriction fragment length polymorphism-polymerase chain reaction. Serum PHT levels were analyzed. RESULTS: The T allele of MDR1 C3435T and GABRG2 C588T gene polymorphism was higher in GS in the Indian population compared with controls. From the data in GS, CT and TT genotype carriers of the MDR1 gene and TT genotype carriers of the GABRG2 gene had more recurrent seizures compared with others. MDR1 T allele carriers in the seizure reoccurrence (SR) group of GS and FS were high compared with the well-controlled seizure group (with no seizures after treatment). TT genotype carriers in SR group were high in FS (with regard to MDR1 gene polymorphism) and GS (with regard to GABRG2 gene polymorphism) compared with a well-controlled seizure group. MDR1 C3435T gene polymorphism affects serum PHT levels (p<0.015). Association of dose PHT ratio and genotype groups of MDR1 C3435T gene polymorphism showed a significant association (p<0.05). MDR1*CC genotype was more common in cases with low serum PHT levels.In addition, it is evident that CT and TT genotype carriers have a high percentage of SR with elevated serum PHT levels. CONCLUSIONS: Our results show that the MDR1 3435T and GABRG2 588T alleles play a role in seizure occurrence. Moreover, the MDR1 3435T allele also affects PHT absorption. We suggest MDR1 C3435T and GABRG2 C588T genotyping would be of value in order to lower the risk of concentration-dependent drug toxicity and for better patient management.
Abstract: Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic nature, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a K(m) value of 140 µm, and naringin inhibited the uptake with an IC(50) value of 18 µm by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC(50) value of 7.5 µm by the Ussing-type chamber method. The estimated IC(50) values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: P-glycoprotein (P-gp), an ATP-dependant efflux pump transports a wide range of substrates across cellular membranes. Earlier studies have identified drug efflux due to the over-expression of P-gp as one of the causes for the resistance of phenytoin, an anti-epileptic drug (AED). While no clear evidence exists on the specific characteristics of phenytoin association with the human P-gp, this study employed structure-based computational approaches to identify its binding site and the underlying interactions. The identified site was validated with that of rhodamine, a widely accepted reference and an experimental probe. Further, an in silico proof-of-concept for phenytoin interactions and its decreased binding affinity with the closed-state of human P-gp model was provided in comparison with other AEDs. This is the first report to provide insights into the phenytoin binding site and possibly better explain its efflux by P-gp.
Abstract: AIM: Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition in pregnant women of drugs cleared by multiple CYP enzymes. METHODS: We expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on in vitro data), CYP2C9 induction (based on phenytoin PK) and CYP2C19 suppression (based on proguanil PK), into the model. This model accounted for gestational age-dependent changes in maternal physiology and hepatic CYP3A, CYP1A2 and CYP2D6 activity. For verification, the pregnancy-related changes in the disposition of methadone (cleared by CYP2B6, 3A and 2C19) and glyburide (cleared by CYP3A, 2C9 and 2C19) were predicted. RESULTS: Predicted mean post-partum to second trimester (PP : T2 ) ratios of methadone AUC, Cmax and Cmin were 1.9, 1.7 and 2.0, vs. observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post-partum to third trimester (PP : T3 ) ratios of methadone AUC, Cmax and Cmin were 2.1, 2.0 and 2.4, vs. observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T3 ratios of glyburide AUC, Cmax and Cmin were 2.6, 2.2 and 7.0 vs. observed values 2.1, 2.2 and 3.2, respectively. CONCLUSIONS: Our PBPK model integrating prior physiological knowledge, in vitro and in vivo data, allowed successful prediction of methadone and glyburide disposition during pregnancy. We propose this expanded PBPK model can be used to evaluate different dosing scenarios, during pregnancy, of drugs cleared by single or multiple CYP enzymes.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: The accurate estimation of "in vivo" inhibition constants () of inhibitors and fraction metabolized () of substrates is highly important for drug-drug interaction (DDI) prediction based on physiologically based pharmacokinetic (PBPK) models. We hypothesized that analysis of the pharmacokinetic alterations of substrate metabolites in addition to the parent drug would enable accurate estimation of in vivoandTwenty-four pharmacokinetic DDIs caused by P450 inhibition were analyzed with PBPK models using an emerging parameter estimation method, the cluster Newton method, which enables efficient estimation of a large number of parameters to describe the pharmacokinetics of parent and metabolized drugs. For each DDI, two analyses were conducted (with or without substrate metabolite data), and the parameter estimates were compared with each other. In 17 out of 24 cases, inclusion of substrate metabolite information in PBPK analysis improved the reliability of bothandImportantly, the estimatedfor the same inhibitor from different DDI studies was generally consistent, suggesting that the estimatedfrom one study can be reliably used for the prediction of untested DDI cases with different victim drugs. Furthermore, a large discrepancy was observed between the reported in vitroand the in vitro estimates for some inhibitors, and the current in vivoestimates might be used as reference values when optimizing in vitro-in vivo extrapolation strategies. These results demonstrated that better use of substrate metabolite information in PBPK analysis of clinical DDI data can improve reliability of top-down parameter estimation and prediction of untested DDIs.