ABSTRACT:CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone (DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16␣-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu 210 to Glu 279 were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16␣-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F-G loops.Cytochromes P450s (P450s) comprise a superfamily of monooxygenases that metabolize a wide variety of exogenous chemicals as well as endogenous substrates such as steroids, fatty acids, and prostaglandins. Multiple forms of P450 have been shown to be present in the liver (Nelson et al., 1996). Among the forms of P450s, CYP3A is the most abundant form in human livers (Kitada et al., 1985a;Shimada et al., 1994), and the human CYP3A subfamily consists of four isoforms: CYP3A4 (Beaune et al., 1986), CYP3A5 (Aoyama et al., 1989), CYP3A7 (Komori et al., 1989), and CYP3A43 (Domanski et al., 2000.CYP3A7 accounts for 30 to 50% of total P450s in the fetal liver (Kitada et al., 1985b;Shimada et al., 1996). CYP3A4 is the major form of P450 expressed in the adult liver, and the expression of CYP3A4 mRNA was not seen in human fetal livers and began to increase after birth (Lacroix et al., 1997). It has been reported that a 5Ј-flanking region from 1 kilobase to the transcriptional start site of the CYP3A7 gene was 91% identical to that of the CYP3A4 gene (Itoh et al., 1992;Hashimoto et al., 1993). Recently, an experiment using HepG2 cells showed that Sp1 and Sp3 bound to the nuclear factor-B-like element of the CYP3A7, but not the CYP3A4 gene, and that the expression of the CYP3A7 gene was cooperatively regulated by Sp1, Sp3, hepatocyte nuclear factor 3, and upstream stimulatory factor 1 (Saito et al., 2001).The nucleotide and amino acid sequences of CYP3A7 (Komori et al., 1989) share 94 and 88% identities, r...
BackgroundConcomitant use of clarithromycin (CAM) and rifampicin (RFP) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease affects the systemic concentrations of both drugs due to CYP3A4–related interactions. To date, however, there has been no report that investigates the long–term relationship between the drug concentrations, CYP3A4 activity, and clinical outcomes. Our aim was to investigate the time course of the drug levels in long–term treatment of subjects with pulmonary MAC disease, and examine the correlation of these concentrations with CYP3A4 activity and clinical outcomes.MethodsUrine and blood samples from nine outpatients with pulmonary MAC disease were collected on days 1, 15, and 29 (for four subjects, sample collections were continued on days 57, 85, 113, 141, 169, 225, 281, 337, and 365). Serum drug concentrations and urinary levels of endogenous cortisol (F) and 6 beta-hydroxycortisol (6βOHF), the metabolite of F by CYP3A4, were measured, and evaluated 6βOHF/F ratio as a CYP3A4 activity marker. In addition, the clinical outcomes of 4 subjects were evaluated based on examination of sputum cultures and chest images.ResultsThe mean 6βOHF/F ratio increased from 2.63 ± 0.85 (n = 9) on the first day to 6.96 ± 1.35 on day 15 and maintained a level more than double initial value thereafter. The serum CAM concentration decreased dramatically from an initial 2.28 ± 0.61 μg/mL to 0.73 ± 0.23 μg/mL on day 15. In contrast, the serum concentration of 14-hydroxy-CAM (M-5), the major metabolite of CAM, increased 2.4-fold by day 15. Thereafter, both CAM and M-5 concentrations remained constant until day 365. The explanation for the low levels of serum CAM in pulmonary MAC disease patients is that RFP-mediated CYP3A4 induction reached a maximum by day 15 and remained high thereafter. Sputum cultures of three of four subjects converted to negative, but relapse occurred in all three cases.ConclusionsOur study demonstrated that serum CAM concentrations in pulmonary MAC disease patients were continuously low because of RFP-mediated CYP3A4 induction, which may be responsible for the unsatisfactory clinical outcomes.
BackgroundLow-dose aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1) and suppresses platelet aggregation. It is effective for secondary prevention of cardiovascular events. Because nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly bind with COX-1, the antiplatelet effects of aspirin may be suppressed when NSAIDs are co-administered. This interaction could be avoided by avoiding simultaneous administration; however, the minimum interval that should separate the administration of aspirin and loxoprofen is not well known. In this study, we investigated how to avoid the influence of NSAIDs on the antiplatelet effects of aspirin. An in vitro experiment was performed to investigate the influence of ibuprofen and loxoprofen at various concentrations on aspirin’s antiplatelet action.MethodsPlatelet aggregation and thromboxane B2 (TXB2) levels were measured after addition of aspirin only and NSAIDs plus aspirin to platelet-rich plasma. NSAIDs were used at their maximum plasma concentrations, the assumed concentration after 6 h (for loxoprofen only), and the assumed concentration after 12 h of taking one clinical dose. Platelet aggregation threshold index (PATI), defined as the putative stimulus concentration giving 50% aggregation, was calculated as an index of aggregation activity.ResultsPATI decreased in ibuprofen plus aspirin group compared to that in the aspirin only group, regardless of ibuprofen concentration. Furthermore, PATI significantly decreased when aspirin was added after loxoprofen-trans-OH addition at the maximum concentration (4.1 ± 0.1 μg/mL), compared to that in aspirin only group (5.9 ± 0.1 μg/mL). PATI showed no significant difference after addition of loxoprofen at the assumed concentration after 6 h (aspirin only group, 5.0 ± 0.5 μg/mL; loxoprofen-trans-OH plus aspirin group, 4.9 ± 0.4 μg/mL).In addition, TXB2 concentration tended to decrease with increasing PATI.ConclusionsIt is desirable to avoid ibuprofen co-administration with the usual once-daily low-dose aspirin therapy; however, a 6-h interval between loxoprofen and aspirin could avoid this potential interaction when loxoprofen is taken before aspirin.
Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca 2 , Mg 2 , etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/ kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. Key words risedronate; mineral water; drug interaction; urine excretion; rat Osteoporosis is a systemic disease characterized by reduced bone mass and structural deterioration of bone tissue, leading to an increased risk of fracture. According to the 2011 Guidelines for the Treatment of Osteoporosis, the number of patients with osteoporosis in the rapidly aging population of Japan is increasing and is now estimated at about 13 million. 1)The occurrence of a fracture significantly impacts a person's daily activities, so pharmacotherapy for the prevention of osteoporosis is recommended for patients who are at high risk of bone fracture. A variety of drugs are available for treating osteoporosis, including calcium agents, active vitamin D 3 , raloxifene, and bisphosphonates (BPs). BPs exhibit particularly potent bone resorption inhibitory activity and are therefore the first-choice drug for treating osteoporosis. 1)Because they inhibit resorption and thus increase bone mineral density, BPs play an important role in treating postmenopausal osteoporosis. The resorption-inhibiting activity of risedronate, a third-generation BP, is reported to be approximately 3000 times that of etidronate, a first-generation BP.2) Recently, risedronate began to be marketed for once per month (75 mg), in addition to daily (2.5 mg) and weekly (17.5 mg) dosing.The variety of mineral waters sold and consumed in Japan has increased in recent years. Annual consumption of mineral water per person in Japan was 25.7 L in 2014 (approximately 3 times that of 15 years ago).3) The consumption of mineral waters in Japan is predicted to increase further in coming years. For orally administered BPs, the package inserts advise patients and health care workers that the bioavailability of the drug may be reduced when taken with mineral waters containing high levels of metal cations (Ca 2+ , Mg 2+, etc.), as a result of chelation (Ajinomoto Co., Inc., Actonel ® package insert [2013/2]). As the hardness of a mineral water depends on its calcium and magnesium conten...
Rifampicin (RFP; 30 mg/kg) was orally administered to fasted or fed rats using ultrapure water as the vehicle, and the influence of food on its pharmacokinetics was investigated. To examine the influence of intragastric pH and RFP solubility, similar experiments were performed using 0.1 M HCl (pH 1.0), 0.1 M phosphate buffer (pH 6.8), or 10% Tween 80 vehicles. Plasma RFP concentrations were measured by HPLC-UV for 24 h. The administration of RFP to fed rats in ultrapure water (10% dissolved) resulted in a significant 40% reduction in the maximum plasma drug concentration (C max ) and area under the concentration-time curve (AUC 0-24 ), as compared with fasted rats (p<0.05). RFP administration in 0.1 M phosphate buffer (10% dissolved) produced approximately 25% lower C max and AUC 0-24 values, as compared with those achieved by RFP in ultrapure water in fasted rats. The administration of RFP in 0.1 M HCl (100% dissolved) to fasted rats increased the AUC 0-24 by approximately 1.8-fold, compared with ultrapure water, suggesting that increasing RFP solubility increased its absorption. The 10% Tween 80 vehicles (60% dissolved) enhanced the absorption of RFP to a similar level as observed when using 0.1 M HCl solution, suggesting that both the improvement in solubility and P-glycoprotein inhibition by Tween 80 increased the absorption. This study suggested that RFP solubility in gastrointestinal fluid may be an important determinant of absorption and that it would be beneficial to change the timing of RFP administration to patients with insufficient clinical outcomes by administration after a meal.Key words rifampicin; pH; solubility; plasma concentration; food; pharmacokinetics The standard treatment for tuberculosis consists of rifampicin (RFP), isoniazid, and pyrazinamide, plus either ethambutol or streptomycin.1) RFP is one of the first-line drugs for tuberculosis, and administration is recommended before breakfast because the absorption of RFP is decreased by food.2) Low serum RFP concentration may cause therapy failure in tuberculosis patients. In patients with insufficient clinical outcomes, its effects were reported to improve when the dose was increased, because this increased the serum RFP concentration.3) Therefore, administration of RFP after a meal can reduce its serum concentration and compromise its efficacy. However, there is an opposite view that maintains that administration of RFP after a meal does not influence efficacy because it does not significantly reduce the maximum plasma drug concentration (C max ) even though the time to C max (T max ) is delayed. 4) In practice, anti-tuberculosis drugs are generally administered together after a meal in order to prevent gastrointestinal dysfunction, to facilitate Directly Observed Treatment-Short course, and to optimize patient adherence. 5,6) Although previous studies have indicated that an elevated gastric pH 7) or an increase in gastric emptying time 8) after a meal can influence RFP absorption, the details are unclear.In the present study, we orally a...
These results suggest that the package inserts of NMEs with a shorter DL tend to be revised earlier and more frequently, and it requires more careful monitoring of safety information after product launch.
BackgroundFluoroquinolones are often used for the treatment of refractory Mycobacterium avium complex (MAC) disease when the clinical efficacy of the recommended regimen, which includes clarithromycin (CAM), rifampicin (RFP), and ethambutol (EB), is insufficient. However, recent in vitro and in vivo studies have suggested that fluoroquinolones decreased the antibacterial activity of CAM when they were administered in combination. In this study, we retrospectively investigated the influence of the combination of CAM and levofloxacin (LVFX) on clinical outcomes for pulmonary MAC disease patients.MethodsPulmonary MAC disease patients from 2010 to 2012 were divided into two groups, those who received LVFX together with CAM (LVFX group) and those who received CAM without LVFX (control group). The number of patients who showed improvement was evaluated at 1, 3, 6 and 12 months after the start of therapy based on bacteriological examination (culture and smear examination) and the bacilli negative conversion rate.ResultsThere were no significant differences between the LVFX group (n = 18, 64.5 ± 6.5 years old) and the control group (n = 57, 71.0 ± 7.0 years old) in terms of gender, age, etiologic agent, baseline culture examination score, concomitant medication, and dosage of each drug. The clinical outcomes in the LVFX group were inferior to those in the control group at all endpoints and observational periods, and we found a significant difference in the percent improvement of the smear examination by fluorescence microscopy method (38 % vs. 83 %) and the bacilli negative conversion rate (38 % vs. 79 %) at 3 months. Our study suggests that the combination of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment. There was no significant difference between both groups in terms of frequency of adverse events.ConclusionThe possibility that combined administration of CAM and LVFX causes unfavorable clinical outcomes for pulmonary MAC disease treatment was suggested.
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