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Francis Brinker ND
1981 NCNM grad, prof at SCNM and U of Az College of Med
Botanical Pharmacokinetic Interactions with Drugs and Botanical Adjuncts
with NSAIDS & Analgesics for Arthritis
Useful Website: http://medicine.iupui.edu/clinpharm/DDIs/table.aspx
**print interaction summary page from moodle
consumer info: http://WWW.DRUGDIGEST.ORG/WPS/PORTAL/DDIGEST
arthritis part of talk at the very end, first part of talk all about drug interactions
interactions with St John's Wort, Ginkgo, Ginseng, Garlic, Peppermint, and as usual Grapefruit

author of books published by Eclectic Med Pub since 1989
involved in ABC and American Herbal Pharmacopoeia since inception 1997

general concepts to apply in review of botanical literature
lots of wrong info out there
most drug/herb info is preliminary
needs to be confirmed
most herbs have no effects
or conflicting studies

induces CYPs-->reduce meds-->tx fails
inhibited CYP-->incr meds-->toxicity
induction takes 10-14 days
inhibition is much faster---relatively immediate
grapefruit juice inhibits 3A4 in no time

he calls CYP's "sips"

ONLY HUMAN RESEARCH REALLY APPLIES TO HUMANS
why use only human research outcomes for P-glycoprotein and cytochrome P450?
extrapolating lab absorption/metabolism is unreliable
animal data may not apply to humans, ex:
licorice extracts inhibited CYPT 3A4 in 3 in vitro studies:
induced same enzyme in mice/rats, no effect in humans
water extracts of black tea inhibited CYPs S2C9, 2C19, 2D6, 3A4 IN VITRO
CYP proteins bind tannins in vitro, tannins are not absorbed in vivo
water extracts with polyphenols bind iron too
tannins well extracted in water, flavonols not so well

pigs and monkeys have similar CYPs to humans
rats and rabbits don't but are more used in research

P GLYCOPROTEIN
transport protein
aka multidrug resistance protein 1
pumps bile salts out of liver and digoxin and some carcinogens out of cells
most active in....list of organs
brings stuff out of cells back into intestinal lumen: the reject system
one mechanism by which we resist toxins
drugs that remain in enterocytes are mostly converted by isozyme 3A4
3A4 is in highest concentration in enterocytes
about 30% of a drug is absorbed, it goes by portal circ to liver
about half of what gets to liver get into cells
so we're down to 15%

Saint John's wort is only known substance that induces P glycoprotein
impact of Pgp induction by StJW on dig absorption requires 1-2 weeks
900mg/day Hypericum extract 4-7:1 with 80% methanol has no effect in dig levels after 1 day
after 10 days this dose reduced peak concentration by 26%
StJW = strong inducer but doesn't work in short term
compared to placebo after 14d, 900mg/d of Ll160 extract reduced dig availability by 25%
powder more effective than encapsulated
lots of forms are completely ineffective, all had hyperforin doses under 5.4mg/d
need standardized hyperforin content over 29mg to induce effect
systemic exposure of bioavailable content is key, varies

other pgp substrates: cimetidine, dexmethason, diltiazem, doxorubicin, erythromycin, etoposide, indinavir, itraconazole, loperaminde, morpine paclitaxel, quinidine, ranitidine, saquinavir, sparflxocin, terfendaine, tetracycline, verapamil, vinblastine

http://medicine.iupui.eduu/clinpharm/DDIs/table.asp

most drugs metab by 3A4 50%, 2C99 and 2C19 25%, 2D6, 1A2, 2E1
in liver 3A, 2C, 1A2 in liver are 40, 25, 18%respectively
80% in intestine in 3A, 15% is 2D
3A5 in 33% of European americans (instead of 3A4)

GENETICS
genetic differences >1%
polymorphisms for 1A2, 2B6, 2C9, 2C19, s#6 and 3A5
1A2 varies 40 fold in humans
great variation between races, greater between species

human metabolism studies have limitations
most studies use single drug dose, small groups, healthy subjects, short term

ECHINACEA AND CAFFEINE
echinacea purpurea
purple coneflower
root extract 1.6gm/d for 8d to 12 subjects increases bioavailability of caffeine
inhibits 1A2
whole plant extract given same but for 28d had no sig effect on caff metab
alkamides are active component in pharm, cause tingling on tongue, may be what affects caff metab


ST JW
n=1 woman needed more theophylline (from 600 to 1600mg) to manage asthma
after taking 300mg/day standardized extract for 2 months
n=? in men no induction of theophylline metab by 1A2 was found with 900mg StJW after 15days

3 studies all different:
caff metab with 900mg/d extract 4% hyperforin shows no sig change w 12 men
in 6 men 6 women same dose-->26% incr in caff metab apparently unrelated to gender
same dose 14d on 16 subjects increased 1A2 in women but not in men

ECH
purpurea root extract
1.6gm/d oral for 8d n=12 incr tolbutaminde bioavialability
rpob inhib 2C9 by 14% (not clinically relevant)
Gorski 2004
this effect often reported in conventional literature as being clinically sig
and reason to avoid herbs

purpurea and angustifolia root extract
tablet combo 4x/da for 14d to 12 men with 23mg/d alkamides
incr S-warfarin clearance (induce 2C9) mild effect
but no effect on coag so not really sig
Toselli 2009

St JW and 2C9 does it inhibit or induce???
7 pts on warfin lower INR with StJW Yue 2000
S-warfarin single dose clearance incr in 12 subjects given StJW for 14d prior and 7d after
Jiant 2005
StJW single dose plasma concentration also reduced
Maurer 1999

lots more studies that don't really say much:
didn't affect ibu level Bell 2007
didn't affect tolbutaminde Wang 2001
two preparations above standardized to hypericin
but not hyperformin which is component involved in mechanism studied
didn't affect tolbutamide Aroid 2005 dose was too low to make any difference

GINKGO
standardized EGb761 is most studied, 24% flavonol glycosides, 6% terpene lactones
360mg/d for 28d in 10 men reduced tolbutamide by 16% Uchica 2006
not affected at 8d Mohutsky 2006
didn't affect S-warfarin at 7d or flurbiprofen after 3 days (again too short for induction)
all three studies dose or time insufficient, mostly time

PANAX QUENQUEFOLIUM and 2C9
2gm powdered root for 21d in 10 healthy subjects reduced warfarin used for 3d
peak INR decr along with peak plasma warfain
compared to 10 taking placebo
very sig effect

2C19 INDUCTION?
yes
Ginkgo in 18 Chinese had sig effect decr omeprazole
15-20% genetic polymorphism for 2C19 so results may not apply to caucasians
another study 12d 12 healthy chinese mephenytoin level decr 8.6%
"good" vs bad metabolizers: studied both, variation in result

no
120mg/d for 12 d didn't change 2C19 or 3A4 on voriconazole in 14 Chinese
120mg bid for 28d didn't change metab of diazepam in Chinese men

if primary isozyme that metabolizes drug is inhibited, other isozymes take up the task

StJW induces 2C19
reduces omeprazole by 38% at 900mg/d
incr metabolites of 2C19 and 3A4
works better in "strong metabolizers"
Wang 2004

at 1day StJW actually inhibited metab of voriconazole
2C19 and 3A4
incr availability in first 10 hours by 22%
after 14 days then 44% reduction in drug
hypericin studied most in last 25 years
inhibits 3A4 immediately but after 10 days induces at a greater level

HYDRASTIS CANADENSIS
goldenseal rhizome/roots
inhibits 2D6
root extract 2.7g/d for 28d in 12 subjects inhib 2D6 metab of debrisoquin by 40%
gurley 2005
3.3gm/d for 14 day inhibit metab by 50%

GARLIC
inhibits 2E1
500mg tid for 28d in 12 young adults of 12 elders
inhib metab of chlorzoxazone
diallyl sulphide gives same effect in 8 adults
amount same as what's in 15 cloves of garlic
an aged garcli extract 10ml didn't change 2E1 metab of acetomenophen
but it works on cholesterol
aged doesn't contains S-allyl-L-cysteine, doesn't have much diallyl sulphide

KAVA
2E1
2g/d for 28 days inhib metab of chlorzoxasone
this would increase ethanol availability
Gurley 2005
doesn't advise using this
more kava-->increased alcohol effect
longterm ethanol induces 2E1

GINKGO
slightly inhibits 2E1
Sun 2002
280mg bid for 12d so large dose minor effect not clinically sig

STJW and 2E1
ages
.3% hypericin 900mg/d
works better for induction in young than in old

ISOZYME 3A4 and GINKGO: mixed results
ginkgo leaf 360mg/d incr midazolam 25% Uchicda 2006
240mg/d 28d 12 young 12 elders didn't work Smith 2001
120mg 18d incr nifedipine peak by 52% Smith 2001 uncharacterized extract
240mg/d 14d decr midazolam Markowitz 2003

3A4 INHIBITION by Panax?
Smith 2001 found it induced at 200mg/d 18d 22=n, uncharacterized extract
Gurley 2002 1.5g/d didn't alter metab, standardized to 5% ginsenosides n=20

MENTHA PIPERITA and 3A4
leaf oil
600mg has sim effect to grapefruit juice (inhibits 3A4) Dresser 2002
methol had no effect Gelal 2005
grapefruit 250ml/d sig inihibitory effect Brinker 2010

HYDRASTIS
2.7G/D 28D 12=n inhib 3A4 Gurley 2005, 2008
4g/d works Wu 2005
Berberine 600mg/d 12d Sandhu 2003
2.3g root pow 14d n=10 didn't work Sandhu 2003

GARLIC
n=10, 2 caps/d 21d induced 3A4 Piscitelli 2002 didn't tell us real dose
1.8g bid 14d no effect Markowitz 2003
Gulrey no effect with 1.2g/d powder 2002

STJW
900mg/d
we know it induces 3A4
women have elevated basal intestinal 3A4 and induction is greater in women by 74% Gurley 2002
to protect babies in womb??
works to reduce midazolam levels 50% taken orally, 20% taken IV, Wang 2001

different preparations of StJW
Mueller 2006
worked with all 3 preparations and one had very little hyperforin
action correlated with flavonoids too, conclusion

StJW induction effect lasts about a week after discontinuing dose
Durr 2000

effect on statins
simvastatin is PgP and 3A4 substrate
900mg 8 healthy males 2 weeks prior to 1 dose
didn't affect pravastatin but reduced simvastatin

hyperforin is key to StJW interactions
induces Pgp and ZCYP by activating pregnane X receptor PXR
PXR regs 2B6, 2C9, 2C19, 3A,
also regs phase II conjugating enzymes GST, UGT, Sts and tranporter prots Pgp, MRP-2, and OATP
Brattson 2009

high hyperforin works better for depression

hypericum induce 2C9?, 2C19, and 3A4

ginkgo induced 2C19 and inhib 3A4

black pepper increases absorption of curcumin content

INFO FOR CONSUMERS
noncommercial, evidence based, consumer health and drug info site
not always up to date, not always accurate, but better than no info at all
gives relative risks in lay language
gives interactions with drugs, alc, tobacco
http://WWW.DRUGDIGEST.ORG/WPS/PORTAL/DDIGEST

****************************
ARTHRITIS PART OF TALK
arthritis common cause of morbidity incl chronic pain, disability, poor quality of life
NSAIDS and analgesics cause SEs in GI, CV, liver
more serious GI adverse effects in elders >65
esp those with prior upper GI events or using low dose aspirin, Laine 2010
he says these groups should not use NSAIDS

CAYENNE TOPICAL
Capsicum frutescens
capsaicin
4x/d, .025% capsaicin cream OTC, effective. Deal 1991
worked even better in RA than in OA but both good
most effective on mild-moderate

ARNICA MONTANA
compared with ibu gel Widrig 2007
on hands, n=204
arnica worked as well as ibu
skin sx were equal

URTICA DIOICA
Randal 2000
frozen leaves applied locally, n=27, thumb, index finger
frozen still has stinging needles
also for knee pain 2008 study Randall
applied fresh leaves to 4 places on knee, used for 1 week
4 mo later some pts still using less analgesic
can grow this in your yard or in a pot
another sp: galeopsifolia, less analgesic effect than with dioica

also nettled cooked and taken po
19 with acute RA, OA, gout, 50g/d stewed leaves taken with subtherapeutic 50mg/d diclofenac for 14d
compared with 17 pts taking 200mg/d diclof
pain and stiffness relief was equivalent
Chrubasic 1997

2009 study
combo of nettle with fish oil, zinc and vit E sig reduced NSAID use
3month followup: mean scores for pain, stiffness, fx, all sig improved

GINGER
used locally
Yip and Tam 2008
oil massaged onto lower extremities works
only works while in use, no lasting effect
taking concentrated extract po can irritate sensitive stomachs
no sig effect taken po Altman & Marcussen
5g/d fresh or .5-1g/day powdered-->stop taking NSAIDS Srivastava & Mustafa 1989
powder worked better than fresh?

talking past end of timeslot, had to be told lecture is over

BOSWELLIA IS GREAT

CURCUMIN
also very effective

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