大家猜！猜！！猜！！！呵呵

1   大家都知道利福平是多个CYP酶如CYP3A4的强诱导剂，而伊曲康唑是CYP3A4强的抑制剂，如果利福平和伊曲康唑合用，对CYP3A4的影响是抑制呢？还是诱导？

2 圣约翰草提取物也是目前公认的CYP3A4的诱导剂，而抗HIV药物利托那韦是强的CYP3A4的抑制剂，通常作为其它抗HIV药物的booster，那么，如果圣约翰草提取物和利托那韦合用，对CYP3A4是诱导作用呢？还是抑制作用？？

有奖猜题啊，哈哈

1. Rifampin更厉害，把itraconazole血浓度降低了很多。是因为itraconazole同时也是CYP酶的底物。CYP酶被Rifampin诱导后就开始疯狂的代谢底物

2.答案同第一题， 诱导作用更强， Norvir的浓度在使用St John's Wort的同时会降低很多很多，因为它也是通过肝脏代谢。

不知答的对不对。

伊曲康唑说明书：“诱酶药物：如利福平和苯妥英可明显降低本品的口服生物利用度，因此，当与诱酶药物共同服用时应监测本品的血浆浓度。”

利福平和异烟肼也是一样吗

路过，学习

同意2楼的说法！！
并提供Stockley’s Drug Interactions一书上的有关内容（英文），如下
Rifampicin very markedly reduces serum itraconazole levels.
This can reduce or abolish the antifungal effects of the itraconazole,
possibly depending on the infection being treated.

临床证据
A patient receiving antitubercular treatment including rifampicin 600 mg
and isoniazid 300 mg daily was also given itraconazole 200 mg daily. After
2 weeks his serum itraconazole levels were negligible (0.011 mg/L).
Even when the dosage was doubled the levels only reached a maximum of
0.056 mg/L. When the antitubercular drugs were stopped his serum itraconazole
level was 3.23 mg/L with a 300 mg daily dose, and 2.35 to 2.6 mg/L with a 200 mg daily dose.9
A later study in 8 other patients confirmed that itraconazole levels were
reduced by rifampicin but the clinical outcome depended on the mycosis
being treated. Four out of 5 patients responded to treatment for a Cryptococcus
neoformans infection, despite undetectable itraconazole levels, apparently
because in vitro there is synergy between the two drugs. In
contrast, 2 patients with coccidioidomycosis failed to respond, and 2 others
with cryptococcosis suffered a relapse or persistence of seborrhoeic
dermatitis (possibly due to M. furfur) while taking both drugs.10 In a patient
patient with AIDS the serum levels of itraconazole 400 to 600 mg daily in
divided doses were undetectable in the presence of rifampicin, and took 3
to 5 days to recover after the rifampicin was stopped.11 Undetectable itraconazole
levels occurred in another patient given rifampicin who was
treated for histoplasmosis.12 In contrast, a study found that the AUC of a
single 100-mg dose of itraconazole was reduced by 80% after 6 healthy
subjects took rifampicin 600 mg daily for 3 days.13 Very markedly reduced
serum itraconazole levels (undetectable in some instances) have
been seen in other healthy subjects and AIDS patients when given rifampicin.
14 Retrospective review of the medical records of 2 patients given
itraconazole and rifampicin indicated that itraconazole was not
effective until rifampicin was stopped, based on the finding of continued
weight loss while on the combination, and a clear weight gain after rifampicin
was stopped.15
处理和重要性
The interaction between itraconazole and rifampicin is established and
clinically important. Monitor the effects of concurrent use, being alert for
the need to increase the itraconazole dosage. The effect on serum itraconazole
levels can be very marked indeed. The clinical importance of this
interaction can apparently depend on the mycosis being treated. Note that
the manufacturer considers that itraconazole should not be used with rifampicin,
since its levels are so markedly reduced.26,27

参考文献
5. Nicolau DP, Crowe HM, Nightingale CH, Quintiliani R. Rifampin-fluconazole interaction in
critically ill patients. Ann Pharmacother (1995) 29, 994–6.
6. Jaruratanasirikul S, Kleepaew A. Lack of effect of fluconazole on the pharmacokinetics of
rifampicin in AIDS patients. J Antimicrob Chemother (1996) 38, 877–80.
7. Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME,
Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS.
Ann Pharmacother (1996) 30, 919–25.
8. Bani-Sadr F, Hoff J, Chiffoleau A, Allavena C, Raffi F. Hypercalcémie sévère chez une patiente
traitée par fluconazole et rifampicine. Presse Med (1998) 27, 860.
9. Blomley M, Teare EL, de Belder A, Thway Y, Weston M. Itraconazole and anti-tuberculosis
drugs. Lancet (1990) ii, 1255.
10. Tucker RM, Denning DW, Hanson LH, Rinaldi MG, Graybill JR, Sharkey PK, Pappagianis
D, Stevens DA. Interaction of azoles with rifampin, phenytoin and carbamazepine: in vitro
and clinical observations. Clin Infect Dis (1992) 14, 165–74.
11. Drayton J, Dickinson G, Rinaldi MG. Coadministration of rifampin and itraconazole leads to
undetectable levels of serum itraconazole. Clin Infect Dis (1994) 18, 266.
12. Hecht FM, Wheat J, Korzun AH, Hafner R, Skahan KJ, Larsen R, Limjoco MT, Simpson M,
Schneider D, Keefer MC, Clark R, Lai KK, Jacobsen JM, Squires K, Bartlett JA, Powderly
W. Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter
trial. J Acquir Immune Defic Syndr Hum Retrovirol (1997) 16, 100–107.
13. Heykants J, Michiels M, Meuldermans W, Monbaliu J, Lavrijsen K, Van Peer A, Levron JC,
Woestenborghs R, Cauwenbergh G. The pharmacokinetics of itraconazole in animals and
man: an overview. In: Fromtling RA, ed. Recent Trends in the Discovery, Development and
Evaluation of Antifungal Agents. SA: JR Prous Science Publishers, 1987 p 223–49.
14. Jaruratanasirikul S, Sriwiriyajan S. Effect of rifampicin on the pharmacokinetics of itraconazole
in normal volunteers and AIDS patients. Eur J Clin Pharmacol (1998) 54, 155–8.
15. Todd JR, Arigala MR, Penn RL, King JW. Case report: possible clinically significant interaction
of itraconazole plus rifampin. AIDS Patient Care STDS (2001) 15, 505–10.
16. Doble N, Shaw R, Rowland-Hill C, Lush M, Warnock DW, Keal EE. Pharmacokinetic study
of the interaction between rifampicin and ketoconazole. J Antimicrob Chemother (1988) 21,
633–5.
17. Brass C, Galgiani JN, Blaschke TF, Defelice R, O’Reilly RA, Stevens DA. Disposition of ketoconazole,
an oral antifungal, in humans. Antimicrob Agents Chemother (1982) 21, 151–8.
18. Engelhard D, Stutman HR,Marks MI. Interaction of ketoconazole with rifampin and isoniazid.
N Engl J Med (1984) 311, 1681–3.
19. Drouhet E, Dupont B. Laboratory and clinical assessment of ketoconazole in deep-seated mycoses.
Am J Med (1983) 74, 30–47.
20. Meunier F. Serum fungistatic and fungicidal activity in volunteers receiving antifungal
agents. Eur J Clin Microbiol (1986) 5, 103–9.
21. Doble N, Hykin P, Shaw R, Keal EE. Pulmonary mycobacterium tuberculosis in acquired immune
deficiency syndrome. BMJ (1985) 291, 849–50.
22. Abadie-Kemmerly S, Pankey GA, Dalvisio JR. Failure of ketoconazole treatment of Blastomyces
dermatidis due to interaction of isoniazid and rifampin. Ann Intern Med (1988) 109,
844–5.
23. Pilheu JA, Galati MR, Yunis AS, De Salvo MC, Negroni R, Garcia Fernandez JC, Mingolla
L, Rubio MC, Masana M, Acevedo C. Interaccion farmacocinetica entre ketoconazol, isoniacida
y rifampicina. Medicina (B Aires) (1989) 49, 43–7.
24. VFEND (Voriconazole). Pfizer Inc. US Prescribing information, November 2006.
25. VFEND (Voriconazole). Pfizer Ltd. UK Summary of product characteristics, July 2007.
26. Sporanox Capsules (Itraconazole). Janssen-Cilag Ltd. UK Summary of product characteristics,
March 2004.
27. Sporanox Capsules (Itraconazole). Janssen. US Prescribing information, June 2006.

呵呵，楼上的回答真的很精彩！！

其实，查阅Medline，这两个问题都有了具体的答案。参见下面：


利福平＋他克莫司＋伊曲康唑（rifampin＋tacrolimus＋itraconazole）

Mori T, Aisa Y, Kato J, et al. Overcoming the effect of rifampin on the tacrolimus metabolism by itraconazole administration in an allogeneic hematopoietic stem cell transplant recipient. Int J Hematol. 2010; 91(3):553-4.
利福平对CYP3A4等具有强的诱导作用，可以降低他克莫司的血浆浓度。因此当合用利福平时应该增加他克莫司的血药浓度。Mori等通过1例异体造血干细胞移植患者，考察了合用伊曲康唑（口服溶液）是否能逆转利福平的酶诱导作用，而无需明显调整他克莫司的剂量。患者为50岁女性，骨髓移植后应用他克莫司和短期的甲氨蝶呤抗排异治疗。调整他克莫司的剂量（iv）使术后前4周维持血药浓度为15–20 ng/ml，然后口服他克莫司维持血药浓度为5–10 ng/ml。术后第33天出现了急性移植物抗宿主病，应用泼尼松龙（1mg/kg治疗7天，逐渐减量，在术后第96天停药）成功控制，在激素治疗中合用了伏立康唑400mg/d口服预防真菌感染。在术后150天，他克莫司的剂量为3mg/d，谷浓度维持在5.5mg/mL。此时患者出现了肺结核，给予利福平300mg/d、厌氧菌300mg/d、乙胺丁醇750mg/d和吡嗪酰胺1200mg/d治疗。开始抗痨治疗不久，他克莫司的谷浓度检测不到，调整剂量为6mg/d仍然达不到检测限（3.0 ng/mL）。为预防真菌感染而给予了口服伊曲康唑200mg/d治疗，发现他克莫司的谷浓度逐渐升高，开始伊曲康唑治疗8天后，他克莫司（剂量3mg/d）的谷浓度达到了 5.7 ng/ml。患者在他克莫司血药浓度无法检测期间没有出现排异反应。合用抗真菌药物期间，抗痨治疗有效，12个月后肺结核治愈。合用药物期间没有临床意义的不良事件，耐受性好。本例患者提示伊曲康唑能逆转利福平对CYP3A的诱导作用而抵消其对CYP3A底物他克莫司的代谢影响。虽未经大规模的临床试验证实，临床可以考虑选择合用。


咪达唑仑+圣约翰草提取物/利托那韦（midazolam+St John's Wort/ritonavir）
Hafner V, Jäger M, Matthée AK, et al. Effect of simultaneous induction and inhibition of CYP3A by St John's Wort and ritonavir on CYP3A activity. Clin Pharmacol Ther. 2010;87(2):191-6.
Hafner等通过12例健康受试者参与的一个随机固定顺序的研究，考察了CYP3A4抑制剂和CYP3A4诱导剂合用对CYP3A4活性的影响。以咪达唑仑为CYP3A4的探针药物，测定：（1）基础水平、或（2）服用单剂量的圣约翰草提取物或单剂量利托那韦后、或（3）服用利托那韦300mg bid+圣约翰草提取物300mg tid共14天后、或（4）在（3）的基础上停药2天后的咪达唑仑的药动学参数。结果发现，与基础水平相比，合用利托那韦和圣约翰草提取物表现为显著的CYP3A4的抑制作用，使静脉给予的咪达唑仑的AUC0-8 h增至基础水平的180%，使口服给予的咪达唑仑的AUC0-6 h增至基础水平的412%；停用两种药物2天后，口服咪达唑仑的AUC0-6h降至合用时的6%；静脉咪达唑仑的AUC0-8h降至合用时的33%。结果提示，合用圣约翰草提取物和利托那韦总体表现为CYP3A4的抑制作用，对口服咪达唑仑的影响更大，说明存在肠道首过效应的抑制，临床应该谨慎合用，并及时调整咪达唑仑的剂量。当停用CYP3A4抑制剂和诱导剂后，残存的诱导效应没有被掩盖，导致CYP3A4底物咪达唑仑的血药浓度降低，临床仍然需要调整剂量，特别是口服药物的剂量。


这些内容也是我在对《药物相互作用基础与临床》一书的update时发现的，拟加入进去。

分享给大家，并且谢谢大家的观注！！

Reduced ketoconazole concentrations have been reported in patients receiving rifampin (1-5). In addition to reduced ketoconazole concentrations, lack of therapeutic response was noted in one patient (3). Lack of clinical response and reduced itraconazole levels were reported in 2 patients receiving rifampin (6,8). In both cases, clinical improvement occurred after rifampin was stopped. In a separate report, itraconazole serum concentrations were decreased in patients receiving concurrent rifampin (7). Although cryptococcal infections were cured in 4 of 5 patients receiving itraconazole and rifampin (possibly due to synergy in killing Cryptococcus neoformans), patients infected with other fungi either did not respond or relapsed while receiving itraconazole with rifampin.  Increased metabolism of several imidazoles by rifamycins was also demonstrated in small trials and case reports. In a study of 6 healthy volunteers, rifampin reduced the AUC of ketoconazole by nearly 80% and lowered peak ketoconazole concentrations. Ketoconazole had no significant effect on rifampin concentrations (5). Coadministration of itraconazole with rifabutin in patients with HIV reduced both the AUC and Cmax of itraconazole by 70% to 75% (11). In a study of 24 healthy men, rifabutin decreased the Cmax and AUC of posaconazole by 43% and 49%, respectively. Rifabutin induction of UDP glucouronidation is suspected in this interaction (12). A 20-year-old male with X-linked chronic granulomatous disease demonstrated decreased posaconazole levels of 57 to 80% when given concurrently with rifampin. Rifampin induction of UDP glucouronidation was also suspected in this case (14). Fluconazole exposure, as measured by AUC, was decreased by 22% in a study of Thai patients with AIDS and cryptococcal meningitis who received concomitant fluconazole with rifampin (13). The authors noted that there were no significant differences in clinical outcome between the 2 groups.  Several imidazoles may decrease the metabolism of rifamycins. A 40-year-old AIDS patient receiving prophylactic rifabutin developed uveities after starting itraconazole therapy. Serum rifabutin concentration was 3-times greater than the expected maximum concentration. Five days after stopping rifabutin, the uveitis had resolved (9). In a study of 24 healthy men, posaconazole increased the Cmax and AUC of rifabutin by 31% and by 72% respectively (12). The official package labeling for posaconazole (Noxafil) states that concurrent administration of posaconazole and rifabutin should be avoided unless benefits outweighs the risk (10). Conversely, a 50% reduction of rifampin concentration occurred in a patient given ketoconazole and rifampin simultaneously, but was unaltered when the drugs were administered 12 hours apart (3).  Close patient monitoring is indicated when imidazoles are co-administered with rifamycins. Increases in imidazole dosage and/or decrease/discontinuation of rifamycin may be necessary.

酮康唑可能使利福平血药浓度降低，而伊曲康唑使其升高！国外《drug interactions facts》说的更清楚！