Pharmacy Blog – Dr Vibore

Cidofovir with probenecid modestly decreased levels of trimethoprim and sulfamethoxazole (co-trimoxazole),and caused moderate increases in didanosine levels, but did not alter fluconazole pharmacokinetics. None of these drugs altered cidofovir pharmacokinetics.

In a study,6 HIV-positive subjects were given co-trimoxazole 960mg daily with a single 3-mg/kg dose of cidofovir with probenecid given on day 7. The AUC and maximum plasma concentrations of both trimethoprim and sulfamethoxazole were decreased by about 30 % and renal clearance was significantly increased. The pharmacokinetics of cidofovir were not affected (See reference number 1).

In a study,6 HIV-positive subjects were given didanosine 100 or 200mg twice daily for 7 days with a single 3-mg/kg dose of cidofovir with probenecid given on day 7. The AUC of didanosine was increased 1.6-fold, but pharmacokinetics of cidofovir were not affected (See reference number 1).

In a study,6 HIV-positive subjects were given fluconazole 100mg daily for 13 days with a single 3-mg/kg dose of cidofovir with probenecid given on day 13. The pharmacokinetics of both drugs were unaffected (See reference number 1).

It was suggested that cidofovir/probenecid might alter renal elimination of these drugs (See reference number 1)

The modest decreases in trimethoprim and sulfamethoxazole levels, and moderate increases in didanosine levels caused by cidofovir are considered unlikely to be clinically relevant because of infrequent dosing schedule of cidofovir/probenecid. No dose adjustments are considered necessary (See reference number 1).

1. Luber A,Lalezari J, Rooney J, Jaffe H, Flaherty J. Drug-drug interaction study with intravenous cidofovir (CDV) and either trimethoprim/sulfamethoxazole (TMP/SMX), didanosine(DDI), or fluconazole (FLU) in HIV-infected individuals. Intersci Conf Antimicrob Agents Chemother (2002) 42, 27.

There appears to be no pharmacokinetic interaction between entecavir and adefovir,lamivudine or tenofovir. However,interactions with other renally excreted drugs cannot be excluded. Nointeractions mediated by cytochrome P450 isoenzymes are expected with entecavir.

Clinical evidence,mechanism, importance and management

Since entecavir is predominantly eliminated by kidney, concurrent use of drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or concurrent drug. However, manufacturers note that there was no pharmacokinetic interaction between entecavir and lamivudine, adefovir or tenofovir at steady state (See reference number 1,2). They say that, apart from these drugs, effects of concurrent use of entecavir with drugs that are excreted renally or affect renal function have not been evaluated, and they therefore recommend that patients should be monitored closely for adverse reactions when entecavir is given (See reference number 1).

The manufacturers say that entecavir is not a substrate,an inducer or an inhibitor of cytochrome P450 isoenzymes. Therefore drug interactions are unlikely to occur with entecavir by this mechanism (See reference number 1,2).

Baraclude (Entecavir). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of productcharacteristics,July 2007.

Baraclude (Entecavir). Bristol-Myers Squibb Company. US Prescribing information,March2007.

No pharmacokinetic interactions occur between foscarnet and didanosine,zalcitabine or zidovudine. The UK manufacturer does not recommend concurrent use of lamivudine and foscarnet.

Clinical evidence,mechanism, importance and management

In a three-phase study,12 HIV-positive patients were given 4 doses of intravenous foscarnet 90 mg/kg, 4 doses of oral didanosine 200 mg, and 4 doses of both drugs together. Based on data obtained from these patients (drug clearance, volume of distribution, half-life, mean residence time), no pharmacokinetic interactions were said to occur between these two drugs. This suggests that no dosage adjustments will be needed during concurrent use (See reference number 1). The antiretroviral effects of foscarnet and didanosine were synergistic (See reference number 2).

Note that US manufacturer does not make any recommendation (See reference number 4)

Intravenous foscarnet 90 mg/kg every 12 hrs and oral zalcitabine 750 micrograms every 8 hrs were given to 12 HIV-positive subjects for 2 days. There were no clinically significant alterations in pharmacokinetics of either drug (See reference number 7). However, manufacturers of zalcitabine(See reference number 8,9) suggested that concurrent use of zalcitabine and foscarnet should be well monitored, because foscarnet may possibly decrease renal clearance of zalcitabine, thereby increasing its serum levels and its toxicity, particularly peripheral neuropathy. The antiretroviral effects of foscarnet and zalcitabine were synergistic (See reference number 2).

No significant alteration in pharmacokinetics of either drug was seen in a 14-day study in 5 AIDS patients given both drugs (See reference number 10). Foscarnet does not appear to affect zidovudine intracellular activation,(See reference number 11) and manufacturer notes that there was no evidence of increased myelotoxicity when foscarnet was used with zidovudine (See reference number 12)

1. Aweeka FT,Mathur V, Dorsey R, Jacobson MA, Martin-Munley S, Pirrung D, Franco J, Lizak P, Johnson J, Gambertoglio J. Concomitant foscarnet and didanosine; a pharmacokinetic(PK) evaluation in patients with HIV disease. American Society of Microbiology 2(See reference number nd) National Conference on Human Retroviruses and Related infections, Washington DC, 1995. Abstract

492.

Palmer S,Harmenberg J, Cox S. Synergistic inhibition of human immunodeficiency virusisolates (including 3’-azido-3’-deoxythymidine-resistant isolates) by foscarnet in combination with 2’,3’-dideoxyinosine or 2’,3’-dideoxycytidine. Antimicrob Agents Chemother (1996) 40, 1285–8.

Epivir (Lamivudine). GlaxoSmithKline UK. UK Summary of product characteristics,March2007.

Epivir (Lamivudine). GlaxoSmithKline. US Prescribing information,October 2006.

Kewn S,Hoggard PG, Sales SD, Johnson MA, Back DJ. The intracellular activation of lamivudine (3TC) and determination of 2’-deoxycytidine-5’-triphosphate (dCTP) pools in thepresence and absence of various drugs in HepG2 cells. Br J Clin Pharmacol (2000) 50, 597–

604.

Hoggard PG,Kewn S, Barry MG, Khoo SH, Back DJ. Effects of drugs on 2’,3’-dideoxy2’,3’-didehydrothymidine phosphorylation in vitro. Antimicrob Agents Chemother (1997) 41, 1231–6.

Aweeka FT,Brody SR, Jacobson M, Botwin K, Martin-Munley S. Is there a pharmacokineticinteraction between foscarnet and zalcitabine during concomitant administration? Clin Ther (1998) 20, 232–43.

Hivid (Zalcitabine). Roche Products Ltd. UK Summary of product characteristics,November2004.

Hivid (Zalcitabine). Roche Pharmaceuticals. US Prescribing information,September 2002.

Aweeka FT,Gambertoglio JG, van der Horst C, Raasch R, Jacobson MA. Pharmacokineticsof concomitantly administered foscarnet and zidovudine for treatment of human immunodeficiency virus infection (AIDS clinical trials group protocol 053). Antimicrob Agents Chemother (1992) 36, 1773–8.

Brody SR,Aweeka FT. Pharmacokinetics of intracellular zidovudine and its phosphorylatedanabolites in the absence and presence of other antiviral agents using an in vitro humanPBMC model. Clin Pharmacol Ther (1997) 61, 149.

Foscavir (Foscarnet). AstraZeneca UK Ltd. UK Summary of product characteristics,May2007.

This section is concerned with drugs used to treat viral infections. These drugs may be grouped by viral infections they are used to treat, and also by drug class (see table 1 below,). Where antivirals affect other drugs interactions are generally covered elsewhere.

The nucleoside analogues are principally eliminated unchanged by kidneys by a process of active tubular secretion as well as glomerular filtration. The few interactions with these drugs mainly involve altered renal clearance (e.g. probenecid),but since they have a wide therapeutic range, even these interactions are of debatable clinical relevance. Cytochrome P450-mediated interactions are not important for this group of drugs.

Treatment of HIV infection commonly requires a combination of 3 to 4 antiretrovirals,termed highly active antiretroviral therapy (HAART). In addition,patients often receive a large number of other drugs for comorbid conditions. This markedly increases risk of drug interactions and complicates their assessment.

CCR5 antagonists are a new class of entry inhibitors currently under development. Maraviroc is nearest to marketing, and is a substrate of CYP3A4. Because of this,CYP3A4 inducers (e.g. efavirenz) lower its levels and CYP3A4 inhibitors (e.g. protease inhibitors) increase its levels.

The fusion inhibitor,enfuvirtide, is a peptide. It does not cause cytochrome P450-mediated drug interactions,and is not affected by potent enzyme inducers (rifampicin) or inhibitors (ritonavir).

The NNRTIs are extensively metabolised by cytochrome P450 isoenzyme system, particularly by CYP3A4. They are also inducers (nevirapine,efavirenz) or inhibitors (delavirdine) of CYP3A4. NNRTIs would therefore be expected to interact with each other,and with protease inhibitors, but not with NRTIs (see below). They also have potential to interact with other drugs metabolised by CYP3A4, and are affected by CYP3A4 inhibitors and inducers. Delavirdine and efavirenz may also inhibit some other P450 isoenzymes. For a summary,see table 2 below,.

NRTIs are prodrugs,which need to be activated by phosphorylation within cells to a triphosphate anabolite. Drugs may therefore interact with NRTIs by increasing or decreasing intracellular activation. NRTIs may also interact with each other by this mechanism. This interaction mechanism is studied in vitro, and clinical data are often not available, or clinical relevance is unclear. Nevertheless, it is generally recommended that drugs inhibiting intracellular activation of NRTIs are not used concurrently (e.g. doxorubicin and stavudine,, or zidovudine and stavudine, ). Hydroxycarbamide, , may increase intracellular activation of NRTIs.

NRTIs are water soluble, and are mainly eliminated by kidneys (didanosine, lamivudine, stavudine, and zalcitabine) or undergo hepatic glucuronidation (abacavir, zidovudine). The few important interactions with these drugs primarily involve altered renal clearance. For zidovudine (and possibly abacavir) some interactions occur via altered glucuronidation, but clinical relevance of these are less clear (e.g. rifampicin,). Cytochrome P450-mediated interactions are not important for this class of drugs.

Some of didanosine preparations (e.g. chewable tablets) are formulated with antacid buffers that are intended to facilitate didanosine absorption by minimising acid-induced hydrolysis in stomach. These preparations can therefore alter absorption of other drugs that are affected by antacids (e.g. azole antifungals,quinolone antibacterials, tetracyclines). This interaction may be minimised by separating administration by at least 2 hours. Alternatively, enteric-coated preparation of didanosine (gastro-resistant capsules) may be used.

The protease inhibitors are extensively metabolised by cytochrome P450 isoenzyme system, particularly by CYP3A4. All of them inhibit CYP3A4, with ritonavir being most potent inhibitor, followed by indinavir, nelfinavir, amprenavir, and saquinavir. The protease inhibitors therefore have potential to interact with other drugs metabolised by CYP3A4, and are also affected by CYP3A4 inhibitors and inducers. Ritonavir and nelfinavir also affect some other cytochrome P450 isoenzymes,as summarised in table 2 below,. In addition,protease inhibitors are substrates as well as inhibitors of P-glycoprotein. Protease inhibitors therefore have potential to interact with each other, and with NNRTIs, but are not likely to interact with NRTIs.

The plasma level of protease inhibitors is thought to be critical in maintaining efficacy and minimising potential for development of viral resistance

Barry M,Mulcahy F, Merry C, Gibbons S, Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet (1999) 36, 289–304.

de Maat MMR,Ekhart GC, Huitema ADR, Koks CHW, Mulder JW, Beijnen JH. Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet (2003) 42, 223–82.

Entecavir,Lamivudine, Telbivudine

Interferon alfa,Peginterferon alfa, Ribavirin

Aciclovir,Famciclovir, Ganciclovir, Penciclovir, Valaciclovir, Valganciclovir

Idoxuridine,Trifluridine, Vidarabine

Cidofovir,Fomivirsen

Foscarnet sodium,Inosine pranobex

Delavirdine,Efavirenz, Nevirapine

Abacavir,Didanosine, Emtricitabine, Lamivudine, Stavudine, Zalcitabine, Zidovudine

Amprenavir,Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir

Oseltamivir,Zanamivir

Amantadine,Rimantadine

2 Summary of effect of protease inhibitors and NNRTIs on cy

CYP3A4,CYP2C19, CYP2C9, CYP2D6

CYP3A4,CYP2D6

CYP3A4,CYP2D6

CYP3A4,CYP2D6

CYP3A4,CYP2D6

CYP3A4,CYP2C9, CYP2D6, CYP2C19

CYP3A4,CYP2B6

CYP3A4,CYP2C9, CYP2C19

Table 1 Classification of Antivirals
Group	Drugs
Antivirals for hepatitis viruses
Nucleoside analogues	Entecavir, Lamivudine, Telbivudine
Nucleotide analogues	Adefovir
Miscellaneous	Interferon alfa, Peginterferon alfa, Ribavirin
Antivirals for herpes viruses
Guanine nucleoside analogues	Aciclovir, Famciclovir, Ganciclovir, Penciclovir, Valaciclovir, Valganciclovir
Other nucleoside analogues	Idoxuridine, Trifluridine, Vidarabine
Nucleotide analogues	Cidofovir, Fomivirsen
Miscellaneous	Foscarnet sodium, Inosine pranobex
Antivirals for HIV infection (antiretrovirals)
CCR5 antagonists	Maraviroc
HIV-fusion inhibitors	Enfuvirtide
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)	Delavirdine, Efavirenz, Nevirapine
Nucleoside reverse transcriptase inhibitors (NRTIs)	Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Zalcitabine, Zidovudine
Nucleotide reverse transcriptase inhibitors	Tenofovir
Protease inhibitors	Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir
Antivirals for influenza
Neuraminidase inhibitors	Oseltamivir, Zanamivir
Others	Amantadine, Rimantadine

Table 2 Summary of the effect of the protease inhibitors and NNRTIs on cy		tochrome P450 isoenzymes
Antiviral	Substrate	Inhibits	Induces
Protease inhibitors
Amprenavir or Fosamprenavir	CYP3A4	CYP3A4
Atazanavir	CYP3A4	CYP3A4
Darunavir	CYP3A4	CYP3A4
Indinavir	CYP3A4	CYP3A4
Lopinavir	CYP3A4	CYP3A4
Nelfinavir	CYP3A4, CYP2C19, CYP2C9, CYP2D6	CYP3A4
Ritonavir	CYP3A4, CYP2D6	CYP3A4, CYP2D6	CYP3A4
Saquinavir	CYP3A4	CYP3A4
Tipranavir	CYP3A4	CYP3A4, CYP2D6	CYP3A4
NNRTIs (Non-nucleoside reverse transcriptase inhibitors)
Delavirdine	CYP3A4, CYP2D6	CYP3A4, CYP2C9, CYP2D6, CYP2C19
Efavirenz	CYP3A4, CYP2B6	CYP3A4, CYP2C9, CYP2C19	CYP3A4
Nevirapine	CYP3A4		CYP3A4

Table 3 Summary of the effect of the protease inhibitors and NNRTIs on cy		tochrome P450 isoenzymes
Antiviral	Substrate	Inhibits	Induces
Protease inhibitors
Amprenavir or Fosamprenavir	CYP3A4	CYP3A4
Atazanavir	CYP3A4	CYP3A4
Darunavir	CYP3A4	CYP3A4
Indinavir	CYP3A4	CYP3A4
Lopinavir	CYP3A4	CYP3A4
Nelfinavir	CYP3A4, CYP2C19, CYP2C9, CYP2D6	CYP3A4
Ritonavir	CYP3A4, CYP2D6	CYP3A4, CYP2D6	CYP3A4
Saquinavir	CYP3A4	CYP3A4
Tipranavir	CYP3A4	CYP3A4, CYP2D6	CYP3A4
NNRTIs (Non-nucleoside reverse transcriptase inhibitors)
Delavirdine	CYP3A4, CYP2D6	CYP3A4, CYP2C9, CYP2D6, CYP2C19
Efavirenz	CYP3A4, CYP2B6	CYP3A4, CYP2C9, CYP2C19	CYP3A4
Nevirapine	CYP3A4		CYP3A4

Clinical evidence,mechanism, importance and management

A man taking perphenazine 8mg twice daily developed marked psychosis soon after starting to take disulfiram 100mg daily (See reference number 1). His serum perphenazine levels had fallen from a range of 2 to 3 nanomol/L to less than 1 nanomol/L. Doubling dosage of perphenazine had little effect, and no substantial clinical improvement or rise in serum levels occurred until he was given intramuscular perphenazine enantate 50mg weekly, at which point levels rose to about 4 nanomol/L. The results of clinical biochemical tests suggested that disulfiram was acting as an enzyme inducer, resulting in increased metabolism and clearance of perphenazine. However,disulfiram normally acts as an enzyme inhibitor. Too little is known to assess general importance of this interaction, and there seems to be no information about an interaction with other phenothiazines.

1. Hansen LB,Larsen N-E. Metabolic interaction between perphenazine and disulfiram. Lancet (1982) ii, 1472.

Clinical evidence,mechanism, importance and management

A man with a history of manic behaviour,taking fluphenazine 15mg daily, had a 25 % reduction in his plasma fluphenazine levels, from 0.93 to

nanograms/mL,over a 13-day period while taking ascorbic acid 500mg twice daily. This was accompanied by a deterioration in his behaviour (See reference number 1). The reason for this effect is not understood. There seem to be no other reports of this interaction with fluphenazine or any other phenothiazine so that this interaction would not appear to be of general importance.

Dysken MW,Cumming RJ, Channon RA, Davis JM. Drug interaction between ascorbic acidand fluphenazine. JAMA (1979) 241, 2008.

Clinical evidence,mechanism, importance and management

A man with a schizoaffective disorder taking lorazepam,orphenadrine, fluvoxamine and fluphenazine decanoate 12.5mg every 2 weeks, developed acute and painful dystonia of trunk, neck, right arm and leg about one week after his last fluphenazine injection and on fourth day of taking spiramycin 6 million units daily for gingivitis. The problem resolved when he was given biperiden (See reference number 1). The reasons for this adverse reaction are not understood, nor is it entirely clear whether this was an interaction between fluphenazine and spiramycin, although author suggested that a causal link existed. This seems to be only report of an alleged interaction between fluphenazine and a macrolide antibacterial and it is therefore of little or no general importance.

1. Benazzi F. Spiramycin-associated acute dystonia during neuroleptic treatment. Can J Psychiatry (1997) 42,665–6.

Ritonavir, and possibly indinavir, are predicted to reduce metabolism of buspirone. A single case report describes Parkinson-like symptoms attributed to concurrent use of buspirone withritonavir and also possibly indinavir.

Clinical evidence,mechanism, importance and management

A 54-year-old man who had been taking high-dose buspirone (40 mg every morning and 30mg every evening) developed Parkinson-like symptoms about 6 weeks after starting to take ritonavir 400mg and indinavir 400 mg,both twice daily. The dose of buspirone was reduced to 15mg three times daily,ritonavir and indinavir were discontinued, and amprenavir 1.2 g twice daily was started. The Parkinson-like symptoms were reduced after about one week and completely resolved after 2 weeks. Buspirone is metabolised by cytochrome P450 isoenzyme CYP3A4, and it is probable that ritonavir, and possibly, but to a lesser extent, indinavir, inhibited metabolism of buspirone resulting in toxic levels (See reference number 1). This appears to be an isolated case report however, manufacturer of buspirone usually recommends that a lower dose of buspirone (2.5 mg twice daily in UK) should be used with potent inhibitors of CYP3A4,(See reference number 2)such as ritonavir.

Clay PG,Adams MM. Pseudo-Parkinson disease secondary to ritonavir-buspirone interaction.Ann Pharmacother (2003) 37, 202–5.

Buspar (Buspirone hydrochloride). Bristol-Myers Pharmaceuticals. UK Summary of productcharacteristics,March 2007.

Rifampicin can cause a marked reduction in plasma levels andeffects of buspirone

In a randomised,study, buspirone 30mg daily was given to 10 healthy subjects, before and after they took rifampicin 600mg daily for 5 days. It was found that rifampicin reduced total AUC of buspirone by almost 90 % and reduced its peak plasma levels by 87%. The pharmacodynamic effects of buspirone were reduced accordingly (as measured by digit symbol substitution,critical flicker fusion, body sway and visual analogue scales for subjective drowsiness) (See reference number 1).

Not fully established, but it is almost certain that rifampicin induces cytochrome P450 isoenzyme CYP3A4 in gut and liver, which metabolises buspirone. Therefore metabolism and clearance of buspirone are increased.

Direct information appears to be limited to this study but it is consistent with way rifampicin interacts with many other drugs. If both drugs are used be alert for need to use an increased buspirone dosage

1. Lambert TS,Kivistö KT, Neuvonen PJ. Concentrations and effects of buspirone are considerably reduced by rifampicin. Br J Clin Pharmacol (1998) 45, 381–5.

St John’s wort decreases plasma levels of quazepam, althoughthis did not reduce its effects in one study. Alprazolam appearsnot to interact,although this needs confirmation. The bioavailability of midazolam was reduced by long-term but not single dosesof St John’s wort.

Clinical evidence,mechanism, importance and management

Alprazolam 1 or 2mg was given to 7 healthy subjects on third day of a 3-day treatment period with St John’s wort (Solaray; hypericin content standardised at 0.3%) 300mg three times daily. The pharmacokinetics of alprazolam were unchanged by St John’s wort, but authors note that 3 days may have been an insufficient time for St John’s wort to fully induce cytochrome P450 isoenzymes (See reference number 1). In another study,16 healthy subjects were given St John’s wort extract 120mg (Esbericum capsules; corresponding to 0.5mg total hypericins and 1.76mg hyperforin) twice daily for 10 days. A single 1mg dose of alprazolam was given on day before treatment with St John’s wort and on last day of treatment. St John’s wort extract at this low dosage and low hyperforin content had no clinically relevant effects on pharmacokinetics of alprazolam, when compared with 12 subjects given placebo.(See reference number 2)

An open-label study in 12 healthy subjects found that a single 900mg dose of St John’s wort had no significant effect on pharmacokinetics of single doses of either oral midazolam 5mg or intravenous midazolam

0.05 mg/kg,although there was a trend for increased oral clearance. However, St John’s wort 300mg three times daily for 14 or 15 days decreased AUC and maximum plasma concentration of oral midazolam by about 50 % and 40%, respectively. Intravenous midazolam was not significantly affected. St John’s wort appears to increase metabolism of oral midazolam by induction of cytochrome P450 isoenzyme CYP3A4 in gut, resulting in reduced midazolam bioavailability (See reference number 3). Similar results were found in another study (See reference number 4).

In a placebo-controlled study,13 healthy subjects were given St John’s wort (TruNature; hypericin content standardised at 0.3%) 300mg three times daily for 14 days with a single 15mg dose of quazepam on day 14. Although St John’s wort did not affect pharmacodynamic effects of quazepam it did decrease quazepam AUC by 26 % and maximum plasma levels by 29%.This was attributed to effects of St John’s wort on cytochrome P450 isoenzyme CYP3A4, by which quazepam is metabolised (See reference number 5).

Markowitz JS,DeVane CL, Boulton DW, Carson SW, Nahas Z, Risch SC. Effect of St John’s wort (Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sci (2000) 66, 133–9.

Arold G,Donath F, Maurer A, Diefenbach K, Bauer S, Henneike-von Zepelin H-H, Friede M,Roots I. No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low hyperforin St John’s wort extract. Planta Med (2005) 71, 331–7.

Wang Z,Gorski C, Hamman MA, Huang S-M, Lesko LJ, Hall SD. The effects of St John’swort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther (2001) 70, 317–26.

Dresser GK,Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochromeP4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther (2003) 73, 41–

50.

5. Kawaguchi A,Ohmori M, Tsuruoka S, Harada K, Miyamori I, Yano R, Nakamura T, MasadaM, Fujimura A. Drug interaction between St John’s wort and quazepam. Br J Clin Pharmacol (2004) 58, 403–10.