Metabolic drug interactions in man : methodological aspects on in vivo studies
Author: Böttiger, Ylva
Date: 2000-06-09
Location: Föreläsningssalen R64, Rehabgatan, plan 6, Huddinge universitetssjukhus
Time: 9.00
Department: Institutionen för medicinsk laboratorievetenskap och teknik / Department of Laboratory Sciences and Technology
Abstract
The aim of this thesis was to investigate methodological aspects on in
vivo metabolic drug interaction studies in man. Five pharmacokinetic
studies in healthy persons or patients are presented. Together, they
represent a set of model studies to evaluate the occurrence of, and
extent of metabolic drug interactions in vivo. They are all based on
previous in vitro findings, and were designed to take advantage of the
current knowledge concerning specificity and selectivity of drug
metabolising enzymes and interindividual differences in drug metabolising
capacity. A special focus was the study of omeprazole as a probe for, and
ketoconazole as an inhibitor of the CYP3A4 enzyme.
Ketoconazole (repeated doses) markedly inhibited the CYP3A4 mediated
sulphoxidation of omeprazole (single doses) in a dose-dependant manner,
in both extensive and poor hydroxylators (CYP2C19) of omeprazole. This
study confirms that omeprazole sulphoxidation is the main metabolic
pathway in individuals devoid of CYP2C19 activity, and shows that these
subjects develop very high omeprazole concentrations during ketoconazole
co-administration. Tolterodine, which is mainly metabolised by CYP2D6,
was given in repeated doses to both poor and extensive metabolisers
(CYP2D6), but did not influence the metabolism (as indicated by
metabolite ratios) of single doses of the probe drugs debrisoquine
(CYP2D6), omeprazole (CYP2C19 and CYP3A4) or caffeine (CYP1A2), given on
three consecutive days. Tolterodine is thus unlikely to inhibit the
metabolism of drugs eliminated via these enzymes. Data from the above
studies, together wit data from two other omeprazole studies, support the
use of omeprazole as a probe for the evaluation of CYP3A4 activity, as
well as its previously suggested use as a probe for CYP2C19. Fluvoxamine
(a CYP1A2 inhibitor), but not ketoconazole, had a significant effect on
the clearance of intravenously administered ropivacaine. This study
confirms in vitro and in vivo pharmacokinetic findings indicating CYP1A2
as the most important enzyme in ropivacaine metabolism, and shows that
CYP1A2 inhibitors may cause clinically relevant interactions with
ropivacaine. Concomitant administration of single doses of sirolimus and
diltiazem lead to increased sirolimus exposure in 16 out of 18 subjects,
presumably by inhibition of intestinal CYP3A4 and/or P-glycoprotein. This
interaction needs further evaluation during steady-state conditions, but
does point to the possibility of other CYP3A4 inhibitors interacting with
sirolimus. Lamotrigine drug interactions were studied in a therapeutic
drug monitoring material including 104 patients. A widespread intra- and
interindividual variation in the concentration/dose ratio for lamotrigine
could largely be explained by pharmacokinetic interactions with
phenytoin, carbamazepine, phenobarbital (all three inducing lamotrigine
metabolism) and valproic acid (an inhibitor of lamotrigine
glucuronidation).
The systematic knowledge concerning drug metabolising pathways and
mechanisms of metabolic drug interactions is growing. Effective and
informative in vitro studies are already in use, and are also being
continuously developed. So far, there is no universally reliable method
to extrapolate in vitro findings to in vivo clinical conditions. However,
with the current knowledge of drug metabolism and a base of in vitro
study methods, it is possible to use a confined number of well designed
interaction studies in vivo, with specific and selective inhibitors and
probe drugs in appropriate doses, given to panels of extensive and poor
metabolisers. Such studies, in combination with routine evaluation of
data from therapeutic drug monitoring, as exemplified in this work, can
provide clinically useful information concerning pharmacokinetic drug
interactions, leading to safer, better individualised and more
cost-effective drug treatment.
List of papers:
I. Böttiger Y, Tybring G, Götharson E, Bertilsson L (1997). "Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin" Clin Pharmacol Ther 62(4): 384-391
Pubmed
II. Brynne N, Böttiger Y, Hallen B, Bertilsson L (1999). "Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole" Br J Clin Pharmacol 47(2): 145-150
Pubmed
III. Arlander E, Ekström G, Alm C, Carrillo JA, Bielenstein M, Böttiger Y, Bertilsson L, Gustafsson LL (1998). "Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors" Clin Pharmacol Ther 64(5): 484-491
Pubmed
IV. Böttiger Y, Säwe J, Brattström C, Tollemar J, Burke J, Häss G, Zimmerman J (2000). "Pharmacokinetic interaction between single, oral doses of diltiazem and sirolimus (rapamycin) in healthy volunteers" (Submitted)
V. Böttiger Y, Svensson JO, Ståhle L (1999). "Lamotrigine drug interactions in a TDM material" Ther Drug Monit 21(2): 171-174
Pubmed
I. Böttiger Y, Tybring G, Götharson E, Bertilsson L (1997). "Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin" Clin Pharmacol Ther 62(4): 384-391
Pubmed
II. Brynne N, Böttiger Y, Hallen B, Bertilsson L (1999). "Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole" Br J Clin Pharmacol 47(2): 145-150
Pubmed
III. Arlander E, Ekström G, Alm C, Carrillo JA, Bielenstein M, Böttiger Y, Bertilsson L, Gustafsson LL (1998). "Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors" Clin Pharmacol Ther 64(5): 484-491
Pubmed
IV. Böttiger Y, Säwe J, Brattström C, Tollemar J, Burke J, Häss G, Zimmerman J (2000). "Pharmacokinetic interaction between single, oral doses of diltiazem and sirolimus (rapamycin) in healthy volunteers" (Submitted)
V. Böttiger Y, Svensson JO, Ståhle L (1999). "Lamotrigine drug interactions in a TDM material" Ther Drug Monit 21(2): 171-174
Pubmed
Issue date: 2000-05-19
Publication year: 2000
ISBN: 91-628-4207-2
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