eP ‘--HERAPEUTICS
`
`A
`
`VOLUME
`
`60 NUMBER
`
`6
`
`DECEMBER
`
`1996
`
`COMMENTARIES
`
`in bioavailability
`Interpatient variability
`related to the extent of absorption:
`for bioavailability and
`Implications
`bioequivalence studies
`
`is
`
`T. Hellriegel,
`Edward
`Walter W. Hauck, PhD
`
`PhD, Thorir D. Bjornsson, MD, PhD, and
`Philadelphia, Pa.
`
`involves the rate and
`Bioavailability, by definition,
`extent to which a drug is absorbed
`into the systemic
`circulation.‘,’ The concept of bioavailability was first
`established during
`the early 1960s and was based on
`the observation
`that an active drug when adminis-
`tered
`in the same dose, but
`formulated
`in either
`comparable or different drug products, oftentimes
`differed
`therapeutically.
`These
`findings
`led to the
`establishment
`of specific regulatory guidelines by
`the U.S. Food and Drug Administration
`(FDA), and
`by 1970 the FDA
`required
`the characterization
`of
`
`of
`the Division of Clinical Pharmacology, Department
`From
`Medicine, Jefferson Medical College of Thomas Jefferson Uni-
`versity.
`Received for publication May 2, 1996; accepted July 15, 1996.
`Reprint requests: Edward T. Hellriegel. PhD, Division of Clinical
`Pharmacology, Thomas Jefferson University, Medical Office
`Building, Room 812, 1100 Walnut St., Philadelphia, PA 19107.
`Clin Pharmacol Ther 1996;60:601-7.
`Copyright 0 1996 by Mosby-Year Book, Inc.
`0009-9236/96/$5.00 + 0 1311176669
`
`for
`for all new drugs intended
`biological availability
`oral use. In more recent years, with
`the passage of
`the Drug Price Competition
`and Patent Restoration
`Act, the FDA began to require
`that all manufactur-
`ers of generic drugs demonstrate bioequivalence be-
`tween
`their product and that of the innovator.
`Since that time, a significant number of develop-
`ments have been made in the areas of bioavailability
`and bioequivalence
`testing by regulatory agencies,
`academia, and the pharmaceutical
`industry. How-
`ever, in spite of these accomplishments a number of
`unresolved
`issues relating
`to study design and data
`analysis methods still exist.3M5 One topic in particular
`that has recently received a great deal of attention
`is
`subject variability. To date, most reports have fo-
`cused primarily on the problem of intrasubject vari-
`ability
`in bioavailability,6-9 whereas
`little emphasis
`has been placed on intersubject variability. Conse-
`quently, no information
`is currently available with
`respect
`to
`the
`relationship
`between
`intersubject
`variability and bioavailability.
`Therefore
`the pur-
`
`601
`
`Hopewell EX1069
`Hopewell v. Merck
`IPR2023-00481
`
`1
`
`

`

`602 Hellrie~el, Bjornsson, and Hauck
`
`CLINICAL
`
`P HABMACOLOGY
`
`&THERAPEUTICS
`DECEMBER 1996
`
`pose of the this article is to examine the relationship
`between absolute bioavailability and the intersubject
`variability
`in bioavailability.
`The hypothesis
`to be
`tested is that the lower a drug’s bioavailability
`is, the
`greater
`the intersubject variability
`in bioavailability.
`If this hypothesis
`is found
`to be true, such a rela-
`tionship,
`in addition
`to being an important
`clinical
`pharmacologic
`principle, could have an impact on
`how bioavailability
`and bioequivalence
`studies are
`designed and interpreted.
`
`METHODS
`to focus on
`this issue, we decided
`To address
`publications
`reporting oral bioavailability
`results in
`one clinical pharmacology
`journal, namely, Clinical
`If this initial
`investi-
`Pharmacology & Therapeutics.
`gation were positive, subsequent
`research could in-
`volve a more complete examination of the literature.
`Data collection. All issues of Clinical Pharmacol-
`ogy & Therapeutics over a 25-year period, or from
`January 1970 through December
`1994, were ex-
`amined. Articles
`that reported oral bioavailability
`data were collected
`and screened. The criteria
`used
`for
`the
`initial screening of journal
`articles
`were as follows:
`(1) the mean absolute bioavail-
`ability, or sufficient data
`to calculate
`the mean
`absolute bioavailability
`of an oral dosage
`form
`(i.e.,
`tablet, capsule, or solution), was provided;
`(2) the intersubject variability
`in bioavailability,
`or
`sufficient data
`to calculate
`the
`intersubject
`vari-
`ability
`in bioavailability,
`of an oral dosage
`form
`was provided;
`(3)
`the sample size (n) was pro-
`vided;
`(4)
`the study was conducted
`in normal
`volunteers
`or in patients with normal kidney and
`liver function;
`and (5) the absolute bioavailability
`was calculated
`from
`the area under
`the plasma,
`serum, or blood drug concentration
`versus
`time
`curve (AUC) and not from urinary excretion data.
`Once
`it was determined
`that each study met
`the
`above
`requirements,
`the
`following
`information
`was recorded
`for
`further
`analysis:
`the
`type of
`subjects (i.e., healthy volunteers
`or patients),
`the
`gender and ages of the subjects,
`the type of assay
`method
`used
`to quantitate
`drug concentrations
`(i.e., chromatographic
`or immunologic),
`the num-
`ber of half-lives over which drug concentrations
`were determined,
`the
`type of oral dosage
`form
`administered
`(i.e.,
`tablet,
`capsule, or solution),
`the measure of variability
`of bioavailability
`re-
`ported
`(i.e., standard
`deviation
`[SD], standard
`error of the mean
`[SEMI, or coefficient
`of varia-
`tion
`[CV]),
`the study design
`implemented
`(i.e.,
`randomized
`crossover,
`crossover-like
`but with
`
`only a single sequence, and/or without mention of
`randomization),
`the mean bioavailability
`(F),
`its
`variability,
`and
`the sample size. If needed,
`the
`variability was calculated
`from data given
`in the
`article. All data were subsequently
`tabulated,
`and
`bioavailability
`versus intersubject
`variability plots
`were prepared
`for statistical analyses.
`Statistical analysis. In this article we use the term
`“intersubject
`variability”
`to refer
`to the total
`inter-
`subject variability. The total
`intersubject variability
`includes
`the
`intrasubject
`variability and a “pure”
`intersubject component of variability. The relation-
`ship between estimated
`intersubject
`coefficient of
`variation and estimated bioavailability was assessed
`by regression analysis without weighting
`for sample
`size. We report Pearson correlation
`coefficients
`(r)
`and show the slopes from
`the linear regressions of
`coefficient of variation
`on bioavailability
`on
`the
`plots.
`
`RESULTS
`identified
`143 papers were
`In this investigation,
`data for
`that
`reported absolute oral bioavailability
`(see Ap-
`100 drugs that satisfied the search criteria
`pendix
`I for a listing of the specific drugs and con-
`tributing
`references).
`In these articles, absolute oral
`bioavailability
`estimates
`ranged
`from
`0.88%
`to
`122%, with a mean bioavailability
`of 55.1%. The
`number of subjects per study ranged
`from
`three
`to
`58, with a mean of 7.80. The relative
`frequencies of
`occurrence of several subject and study characteris-
`tics among these articles are summarized
`in Table I.
`Frequency
`ratios and percentages
`for all variables
`are based on a total of 143 references, with
`the
`exception of formulation
`type, which
`is based on a
`total of 149. The reason for this difference
`is that six
`studies
`reported absolute bioavailability
`estimates
`for two different oral formulations.
`I, the
`in Table
`Subject characteristics. As shown
`vast majority
`of
`the studies were conducted
`in
`normal
`volunteers
`(80.4%), whereas a substan-
`tially smaller proportion
`were carried out
`in a
`patient population
`(17.5%). Even fewer
`investiga-
`tions were conducted with normal volunteers and
`patients
`together
`in
`the same study
`(2.1%). A
`similar disparity was evident with
`respect
`to the
`gender of the subjects used, with 51.0% of
`the
`studies being conducted
`in men only and just 3.5%
`being conducted
`in women only. A subject popu-
`lation composed of both males and
`females was
`used in 35.7% of the investigations.
`In most stud-
`ies, the age of the subjects ranged
`from 20 to 60
`years of age (67.1%), whereas only 0.7% were
`
`2
`
`

`

`CLINICAL PHARMACOLOGY
`
`& THISAPEUTICS
`
`VOLUME
`
`60, NUMRER 6
`
`Hellriegel, Bjornsson, and Hnucb
`
`603
`
`Table I. Relative frequencies of occurrence of
`various subject and study characteristics among 143
`references reporting absolute oral bioavailability data
`in Clinical Pharmacology & Therapeutics between
`1970 and 1994
`
`Parameter
`
`Frequency Percentage
`
`125
`
`100
`
`i
`
`t
`
`.
`
`.
`
`.
`
`Subjects
`Not reported
`Healthy volunteers
`Patients
`Mixed
`
`Gender
`Not reported
`Male
`Female
`Mixed
`
`Age W
`Not reported
`<20
`20-60
`>60
`Mixed
`
`Assay method
`Not reported
`Chromatographic
`Immunologic
`Other
`
`(no. of half-lives)
`Sampling
`Not reported
`>2 (but ~3)
`>3 (but ~4)
`>4 (but 6)
`>5
`
`Formulation
`Not reported
`Tablet
`Capsule
`Solution
`
`reported
`Variability
`Not reported
`SD
`SEM
`cv
`
`Study design
`Not reported
`1970-1978
`1979-1987
`1988-1994
`Crossover
`1970-1978
`1979-1987
`1988-1994
`Randomized crossover
`1970-197s
`1979-1987
`1988-1994
`
`o/143
`115/143
`251143
`31143
`
`141143
`731143
`51143
`511143
`
`91143
`o/143
`961143
`11143
`371143
`
`11143
`1071143
`191143
`16/143
`
`31143
`321143
`331143
`241143
`411143
`
`411149
`531149
`241149
`311149
`
`161143
`831143
`391143
`51143
`
`14134
`22185
`4124
`
`1 l/34
`26185
`6124
`
`9134
`37/a
`14124
`
`0.0
`80.4
`17.5
`2.1
`
`9.8
`51.0
`
`3::;
`
`6.3
`0.0
`67.1
`0.7
`25.9
`
`0.7
`74.8
`13.3
`11.2
`
`2.1
`22.4
`23.1
`16.8
`35.6
`
`27.5
`35.6
`16.1
`20.8
`
`11.2
`58.0
`27.3
`3.5
`
`41.2
`25.9
`16.7
`
`32.4
`30.6
`25.0
`
`26.4
`43.5
`58.3
`
`25
`
`.
`
`.
`
`.
`
`.-..
`
`‘,
`
`l
`
`Of
`0
`
`I
`
`25
`
`I
`
`50
`
`I
`
`75
`
`I
`
`100
`
`F
`
`(%)
`
`\
`
`I-.
`
`125
`
`I
`
`150
`
`Fig. 1. Relationship between absolute bioavailability (F)
`and intersubject variability (CV) in absolute bioavailabil-
`ity for all studies evaluated (n = 149). Data were obtained
`from a total of 143 references reporting absolute oral
`bioavailability data in Clinical Pharmacology
`& Therapeu-
`tics between 1970 and 1994. The total number of drugs
`studied was 100, the majority of which were cardiovascular
`system agents (38) central nervous system agents (25)
`and antiinfective agents (9).
`
`than 60. None of
`carried out with subjects older
`the studies determined
`oral bioavailability
`exclu
`sively in subjects below
`the age of 20. However,
`several studies
`(25.9%) were conducted with a
`combination
`of subjects from all three age groups.
`Relationships between bioavailability and variability.
`Fig. 1 illustrates
`the relationship between absolute
`bioavailability
`(F) and intersubject variability
`(CV)
`in absolute bioavailability
`for all 149 data points.
`Regression analysis of the data revealed a significant
`inverse linear relationship between
`the two variables
`of interest
`(p < 0.001; r = 0.624). This finding
`is
`consistent with our hypothesis
`that
`the
`lower a
`drug’s bioavailability,
`the greater
`the
`intersubject
`variability
`in bioavailability, and the higher a drug’s
`bioavailability,
`the smaller the intersubject variabil-
`ity in this parameter.
`The relationship between absolute bioavailability
`(F) and
`intersubject
`variability
`(CV)
`in absolute
`bioavailability by type of subjects is shown in Fig. 2.
`When
`the data were stratified according
`to subject
`type, regression analysis demonstrated
`an inverse
`linear relationship between
`the two variables of in-
`
`3
`
`

`

`604 Hellrie~el, Bjornsson, and Hawk
`
`CLINICAL
`
`PHARMACOLOGY
`
`&THERAPEUTICS
`DECEMBER 1996
`
`125
`
`100
`
`1
`
`-
`
`.
`
`d
`
`.
`
`125
`
`100
`
`75
`
`50
`
`2.5
`
`s
`
`2
`
`0
`
`0
`
`25
`
`50
`
`75
`
`100
`
`125
`
`150
`
`0
`
`25
`
`50
`
`75
`
`100
`
`125
`
`150
`
`F
`
`(%I
`
`F 6)
`
`Fig. 2. Relationship between absolute bioavailability (F)
`and intersubject variability (CV) in absolute bioavailabil-
`ity by type of subjects (n = 146). See legend of Fig. 1 for
`source of data.
`
`Fig. 3. Relationship between absolute bioavailability (F)
`and intersubject variability (CV) in absolute bioavailabil-
`ity by gender (n = 129). See legend of Fig. 1 for source of
`data.
`
`(p < 0.001; r =
`terest for both healthy volunteers
`0.614) and patients
`(p < 0.001; r = 0.674).
`Fig. 3 shows the relationship
`between absolute
`bioavailability
`(F) and intersubject variability
`(CV)
`in absolute bioavailability
`by gender. Because few
`investigations were conducted with
`female subjects
`(3.5%), a direct comparison
`between men and
`women was precluded. Therefore
`an analysis was
`done to compare studies conducted solely in male
`subjects with
`those conducted
`in a subject popula-
`tion made up of both genders. Regression analysis
`showed a significant
`relationship between bioavail-
`ability and interpatient
`variability
`in bioavailability
`for studies conducted
`in male subjects (p < 0.001;
`r = 0.625), as well as for
`those conducted
`in a
`subject population
`comprised of both men and
`women @ < 0.001; r = 0.541).
`
`DISCUSSION
`Over the past several decades, bioavailability and
`bioequivalence
`studies have become an important
`part of drug development. As a result, much interest
`has focused on
`the science of bioavailability
`and
`bioequivalence
`testing. One area in particular
`that
`has recently received a great deal of interest
`is that
`of subject variability.6-g
`In this investigation, we ex-
`amined
`the relationship between absolute oral bio-
`
`in this parameter. Our
`availability and the variability
`results clearly show a significant
`relationship
`be-
`tween the absolute bioavailability of an oral dosage
`form and
`its intersubject
`coefficient of variation.
`Specifically, we observed an inverse association be-
`tween the absolute bioavailability of a drug and the
`total variability
`in absolute bioavailability.
`The total intersubject variability of bioavailability,
`as reported here, has both intrasubject and intersub-
`ject components. The design of absolute bioavail-
`ability studies does not permit separate estimation
`of these two components of variability. We can only
`speculate
`that each component
`follows
`the same
`inverse association as found here for the total vari-
`ability.
`In contrast, bioequivalence
`studies yield es-
`timates of the intrasubject variability
`(see Steinjans
`et al.’ for a tabulation of some of these variabilities).
`These findings have a number of important
`impli-
`cations. First, because most bioequivalence
`(com-
`parative bioavailability)
`studies today are conducted
`with a randomized
`crossover design with a single
`panel of subjects, only the intrasubject component
`of variability contributes
`to the error in determining
`relative bioavailability.
`If the relationship we have
`observed here also applies to the intrasubject com-
`ponent of variability,
`low bioavailability
`products
`will require
`larger studies (more subjects).
`
`4
`
`

`

`CLINICAL
`VOLUME
`
`PHAIWACOLOGY
`60, NUMBER 6
`
`& THER4PEUTICS
`
`Hellriegel, Bjornsson, and Hawk
`
`605
`
`clinical implications.
`Second, there are important
`Because the intersubject component of variability
`is
`almost always larger than the intrasubject component,
`we can be reasonably confident
`that the results we
`have reported here do apply to the intersubject com-
`ponent. The consequence
`is that low bioavailability
`products will show more patient-to-patient
`variability
`than more bioavailable products. Therefore
`it is im-
`portant
`that care be taken when prescribing low bio-
`availability drugs; these are the products for which the
`results of the bioavailability studies and even previous
`clinical experience are less likely to apply to a new
`patient. This is especially true when considering
`low
`bioavailability drugs with a narrow “therapeutic win-
`dow” for which there is an increased risk of toxicity.
`Another
`potential
`clinical
`implication
`concerns
`regulatory criteria
`for bioequivalence. Current cri-
`teria
`in the United States, Canada, and Europe
`require only evidence of equivalence
`in average bio-
`availability of generic drug products
`to the innovator
`product.
`It
`is conceivable
`that
`two drug products
`that are similar in average bioavailability may differ
`in variability of bioavailability.
`This would seem to
`be of particular potential
`for products with low bio-
`availability
`(and hence often with high variability).
`To address this problem,
`it has been suggested that,
`in addition
`to establishing bioequivalence
`in average
`bioavailability,
`bioequivalence
`in variability should
`also be confirmed.‘0-12
`the
`in the study was that
`An
`interesting
`finding
`relationship between absolute bioavailability and in-
`tersubject variability
`in bioavailability was not influ-
`enced by subject type or gender.
`In recent years, the
`issue of gender-related
`differences
`in bioavailability
`has received much attention
`and, until
`recently,
`women were typically excluded
`from bioavailability
`and bioequivalence
`trials. One of the primary
`rea-
`sons for the exclusion of women was the belief
`that
`hormonal
`fluctuation during different phases of the
`menstrual cycle may increase variability. However, a
`recent review of the literature by the FDA revealed
`little evidence
`for an effect of menstrual
`cycle on
`the variability
`of pharmacokinetic
`parameters
`of
`drugs.13 Similar findings were reported by Chen and
`Williams,’ who observed no difference between men
`and women
`in within-subject
`variability
`for AUC
`and peak plasma drug concentration
`after oral ad-
`ministration
`(C,,,). The relationship between abso-
`lute bioavailability and the intersubject variability
`in
`bioavailability
`according
`to subject
`type has been
`less well studied. However, based on the data from
`the present investigation,
`it appears that the extent of
`
`is independent of the type
`variability in this parameter
`of subjects used. More detailed studies will be neces-
`sary to determine
`if such differences do in fact exist.
`Clearly, variability
`is important.
`In conducting
`this
`review, we found
`that many authors
`(11%) did not
`recognize
`this importance:
`their articles did not re-
`port the variability of the product, although
`it could
`be calculated
`from
`the data provided. Of those ar-
`ticles that did report variability, many (27% of all
`articles) reported
`the standard error of the mean.
`The standard error
`is a measure of the precision
`with which
`the average bioavailability
`is estimated
`and depends,
`in part, on
`the sample size of
`the
`study. The variability of the bioavailability
`of
`the
`product
`is estimated by the standard deviation or
`the coefficient of variation, and we recommend
`that
`reporting of either be the standard.
`Finally, we want to add that this review highlights
`the
`improvement
`in the conduct
`in absolute bio-
`availability studies during
`the years covered by this
`review.
`In the later years, the majority of studies
`were designed as randomized
`crossover studies. In
`earlier years, randomization was much rarer; often,
`the article did not mention design at all. Because it
`is generally assumed that randomized crossover de-
`signs are superior, one may expect less variability
`to
`result in the estimation of bioavailability
`from
`these
`types of studies compared with
`those
`that
`imple-
`ment a crossover-like design but with only a single
`sequence of drug administration. However,
`it is in-
`teresting
`to note that when these two types of study
`designs were compared with use of data from
`the
`present analysis, little difference was observed be-
`tween
`them with
`respect to their
`relationships be-
`tween bioavailability
`and coefficient of variation
`(data not shown).
`investigation
`this
`results of
`In summary,
`the
`clearly show a significant
`inverse linear relationship
`between
`the bioavailability of a drug and its coeffi-
`cient of variation. Moreover,
`similar
`relationships
`were observed when the data was stratified accord-
`ing to subject type and gender. These findings,
`in
`addition
`to being of clinical significance, could have
`an impact on how bioavailability and bioequivalence
`studies are designed and interpreted.
`
`References
`1. Gibaldi M. Biopharmaceutics and clinical pharmaco-
`kinetics. 4th ed. Philadelphia: Lea & Febiger, 1991.
`2. Rowland M, Tozer TN. Clinical pharmacokinetics:
`concepts and applications. 2nd ed. Philadelphia: Lea
`& Febiger, 1989.
`
`5
`
`

`

`606 Hellriegel, Bjornsson, and Hawk
`
`CLINICAL
`
`PHARMACOLOGY
`
`& THERAPEUTICS
`
`DECEMBER 1996
`
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`Hauck WW, Anderson S. Types of bioequivalence
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`Liu JP. Bioequivalence and intrasubject variability.
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`Reg AlIairs 1983;1:109-32.
`Steinjans VW, Sauter R, Hauschke D, Diletti E,
`Schall R, Luus HG, et al. Reference tables for the
`intrasubject coefficient of variation in bioequivalence
`studies. Int J Clin Pharmacol Ther 1995;33:427-30.
`Haynes JD. Statistical simulation study of new pro-
`posed uniformity
`requirement
`for bioequivalence
`studies. J Pharm Sci 1981;70:673-5.
`Anderson S, Hauck WW. Consideration of individual
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`259-73.
`Lui JP, Chow SC. On the assessment of variability in
`bioavailability/bioequivalence studies. Commun Stat,
`Part A 1992;21:2591.
`Department of Health and Human Services, Food
`and Drug Administration. Guideline for the study and
`evaluation gender differences in clinical evaluation of
`drugs. Federal Register Notice, July 22, 1993;58(139):
`39406-16.
`
`I
`APPENDIX
`List of drugs and contributing references used in the
`present analysis. All references were published in Clinical
`& Therapeutics between 1970 and 1994.
`Pharmacology
`Cardiovascular system agents
`Acebtiolol: Meffin PJ et al. 1978;24:542-7.
`N-Acetylprocainamide: Strong JM et al. 1975;18:613-22;
`Atkinson AJ et al. 1989;46:182-9.
`Amioaiwone: Pourbaix S et al. 1985;37:118-23.
`Amlodipine: Abernethy DR et al. 1990;48:76-86.
`Amosulalol: Nakashima M et al. 1984;36:436-43.
`Atenolol: Mason WD et al. 1979;25:408-15.
`Bidisomide: Page RL et al. 1992$1:371-g.
`Bretylium tosylate (bretylium tosilate): Anderson JL et al.
`1980;28:468-78.
`Clonidine: Davies DS et al. 1976;21:593-601.
`Digoxin: Huffman DH et al. 1974;16:310-7; Marcus FI
`et al. 1976;20:253-9; Cusack B et al. 1979;25:772-6; Hager
`WD et al. 1981;30:594-9.
`Dilevalol: Tenero DM et al. 1989;46:648-56.
`Dipyridamole: Mahony C et al. 1982;31:330-8.
`
`Encainide: Bergstrand RH et al. 1986;40:148-54.
`Felodipine: Edgar B et al. 1985; 38:205-11.
`Fenoximone: Alken RG et al. 1984;36:209-16.
`Hydrulazine: Shepherd AMM et al. 1980;28:804-11;
`Reece PA et al. 1980;28:769-78; Crawford MH et al.
`1985;38:538-43.
`Zsosorbide din&ate: Straehl P, Galeazzi RL 1985;38:
`140-9.
`Zsosorbide Smononitrate: Major RM et al. 1984;35:653-
`59.
`Labetalol: Lalonde RL et al. 1990;48:509-19.
`Lidocaine: Boyes RN et al. 1970;12:105-6; deBoer
`AG et al. 1979;26:701-9; Huet PM, Lelorier J 1980;28:
`208-15.
`Medroxalol: Haegele KD et al. 1983;3:785-91.
`Metoprolol: Hogstedt S et al. 1985;37:688-92.
`Mexiletine: Haselbarth V et al. 1981;29:729-36.
`Nicainoprol: Ishizaki T et al. 1987;42:525-34.
`Nifdipine: Kleinbloesem CH et al. 1985;37:563-74;
`Kleinbloesem CH et al. 1986;40:21-8.
`Nisoldipine: van Harten J et al. 1988;43:332-41.
`Oxprenolol: Mason WD, Winer N 1976;20:401-12.
`Pamatolol: Carruthers SG et al. 1979;26:682-5.
`Pindolol: Chau N et al. 1977;22:505-10.
`Pirmenol: Hammill SC et al. 1982;32:686-91.
`Pruzosin: Chau N et al. 1980;28:6-11; Grahnen A et al.
`1981;30:439-46.
`Procainamide: Graffner C et al. 1974;17:414-23.
`Propafenone: Haefeli EW et al. 1990;48:245-54.
`Propranolol: Vestal RE et al. 1979;25:19-24; Jackman
`GP et al. 1981;30:291-6; Wilson TW et al. 1982;32:676-85;
`Wells PG et al. 1983;33:603-8; Olanoff LS et al. 1986;40:
`408-14.
`Quinidine: Ueda CT et al. 1976;20:260-5.
`Timolol: Wilson TW et al. 1982;32:676-85.
`Tocuinide: Lalka D et al. 1976;19:757-66.
`Verupamil: Freedman SB et al. 1981;30:644-52; Kates
`RE et al. 1981;30:44-51; McAllister RG, Kirsten EB 1982;
`31:418-26; Smith MS et al. 1984;36:551-4; Abernethy DH
`et al. 1985;38:342-9.
`
`Central nervous system agents
`Amitriptyline: Schulz P et al. 1983;33:360-6.
`Amobarbital: Inaba T et al. 1976;20:439-44.
`Cujkine: Cheng WSC et al. 1990;47:516-24.
`Codeine: Guay DRP et al. 1988;43:63-71.
`Huloperidol: Holley FO et al. 1983;33:477-84.
`Zmipramine: Gram LF, Christiansen J 1975;17:555-63;
`Abernethy DR et al. 1984;35:792-97; Ciraulo DA et al.
`1988;43:509-18.
`Loruzepum: Greenblatt DJ et al. 1979;26:103-13; Mor-
`rison G et al. 1984;35:646-52; Herman RJ et al. 1989;46:
`18-25.
`Lormetazepam: Humpel M et al. 1980;28673-9.
`
`6
`
`

`

`CLINICAL
`VOLUME
`
`PHARMACDLOGY
`60, NUMBER 6
`
`& THERAPEKJTKS
`
`Hellrie~el, Bjomsson, and Hawk
`
`607
`
`(‘pethidine): Verbeeck RK et al. 1981;30:619-
`Meperidine
`28; Pond SM et al. 1981;30:83-8; Pond SM, Kretschzmar
`KM 1981;30:680-6;Herman RJ et al. 1985;37:19-24.
`Miduzohzm: Allonen H et al. 1981;30:653-61; Klotz U,
`Ziegler G 1982;32:107-12; Fee JPH et al. 1987;41:80-4;
`Mandema JW et al. 1992;51:715-28; Olkkola KT et al.
`1993;53:298-305.
`Schoerlin MP et al. 1987;42:395-404;
`Moclobemide:
`Schoerlin MP et al. 1991;49:32-8.
`Morphine: Sawe J et al. 1981;30:629-35; Osborne R et
`al. 1990;47:12-9.
`Jaillon P et al. 1989;46:226-33.
`Nalbuphine:
`Nicotine: Benowitz NL et al. 1991;49:270-7.
`Nortriptyline: Gram LF, Fredricson Overo K. 1975;188:
`305-14.
`Nomifensine: Lindberg RL et al. 1986;39:384-8.
`Oxycodone: Leow KP et al. 199352487-95.
`Pentazocine: Ehrnebo M et al. 1977;22:888-92.
`Phenytoin: Gugler R et al. 1975;19:135-42; Jung D et al.
`1980;28:479-85; Sandor P et al. 1981;30:390-7.
`Z’yridostigmine: Breyer-Pfaff U et al. 1985;37:495-501.
`Risperidone: Huang ML et al. 1993;54:257-68.
`(THC): Ohlsson A et al. 1980;28:
`Tetrahydrocannabinol
`409-16.
`Truzodone: Greenblatt DJ et al. 1987;42:193-200.
`Abernethy DR et al. 1984;35:348-53.
`Trimipramine:
`VuZproute: Klotz U, Antonin KH 1977;21:736-43.
`
`Urinary tract system agents
`Bumetunide: Lau HSH et al. 1986;39:635-45; Cook JA
`et al. 1988;44:487-500.
`Furosemide: Kelly MR et al. 1973;15:178-86; Rane A et
`al. 1978;24:199-207; Villeneuve JP et al. 1986;40:14-20.
`
`Hepatogastroenterologic agents
`Cimetidine: Sonne J et al. 1981;29:191-7.
`Nizatidine: Knadler MP et al. 1987;42:514-20; Aronoff
`GR et al. 1988;43:688-95.
`Oxmetidine: Gugler R et al. 1982;31:501-8.
`Runitidine: Chau N et al. 1982;31:770-4; Garg DC et al.
`1983;33:445-52.
`
`Antineoplastic and immunomodulating agents
`(ciclosporin): Ptachcinski RJ et al. 1985;38:
`Cyclosporine
`296-300; Frey FJ et al. 1988;43:55-62; Hebert MF et al.
`1992;52:453-7; Tan KKC et al. 1993;53:544-54.
`Haegele KD et al. 1981;30:
`Dtjhroromethylornithine:
`210-7.
`Zimm S et al. 1983;34:810-7.
`6-Mercuptopurine:
`Methotrewte: Stewart CF et al. 1990:47:540-6.
`
`Endocrine and metabolism agents
`Dexamethusone: Duggan DE et al. 1975;18:205-9.
`Flunisolide: Chaplin MD et al. 1980;27:402-13.
`Derendorf H et al. 1985;37:502-7.
`Methylprednisolone:
`(norethisterone): Back DJ et al. 1978;24:
`Norethindrone
`448-53.
`Prednisolone: Petereit LB, Meikle AW 1977;22:912-6;
`Tanner A et al. 1979;25:571-8.
`
`Respiratory system and antiallergy agents
`Spector R et al. 1980;28:229-34.
`Diphenhydramine:
`Methapyrilene: Calandre EP et al. 1981;29:527-32.
`Terbutuline: Bredberg U et al. 1992;52:239-48.
`Theophylline: Mitenko PA, Ogilvie RI 1974;6:720-6.
`
`Miscellaneous agents
`Uges DRA et al. 1982;31:587-93.
`4-Aminopyridine:
`Clodronate: Yakatan GJ et al. 1982;31:402-10.
`Bobik A et al. 1981;30:673-9;
`Dihydroergotamine:
`Woodcock BG et al. 1982;32:622-7.
`Janssen U et al. 1989;46:317-23.
`Flumazenil:
`Fluoride: Ekstrand J et al. 1978;23:329-37.
`(indometacin): Alvan G et al. 1975;18:364-
`Zndomethacin
`73.
`PentoxtBlfine: Beermann B et al. 1985;37:25-8; Rames
`A et al. 1990;47:354-9.
`Wurfarin: Breckenridge A, Orme M 1973;14:955-61.
`d-Xylose: Wotwag EM et al. 1987:41:351-7.
`
`Klecker RW et al. 1987;41:
`
`(amoxicilline):
`
`Zarowny D et al. 1974;16:
`
`Antiinfectives
`Amoxicillin
`1045-51.
`3’-Azido3’-deoxythymidine:
`407-12.
`Cloxucillin: Nauta EH, Mattie H 1976;20:98-108.
`DicZoxacilZin: Nauta EH, Mattie H 1976;20:98-108.
`Didanosine: Knupp CA et al. 1991;49:523-35.
`Flucytosine: Cutler RE et al. 1978;24:333-42.
`Jensen JC, Gugler R 1983;34:481-7.
`Metronidazole:
`Hoener BA, Patterson SE 1981;29:808-
`Nitrojkruntoin:
`16.
`Ribavirin: Lertora JJL et al. 1991;50:442-9.
`
`7
`
`