Dose adaptation for liver disease is important in patients treated with antineoplastic drugs because of the high prevalence of impaired liver function in this population and the dose-dependent, frequently serious adverse effects of these drugs. We classified the antineoplastic drugs marketed in Switzerland at the end of 2004 according to their bioavailability and/or hepatic extraction to predict their kinetic behaviour in patients with decreased liver function. This prediction was compared with kinetic studies carried out with these drugs in patients with liver disease. The studies were identified by a structured, computer-based literature search. Of the 69 drugs identified, 52 had a predominant extrarenal (in most cases hepatic) metabolism and/or excretion. For 49 drugs, hepatic extraction could be calculated and/or bioavailability data were available, allowing classification according to hepatic extraction. For 18 drugs, kinetic studies have been reported in patients with impaired liver function, with the findings generally resulting in quantitative recommendations for adaptation of the dosage. In particular, recommendations are precise for 16 drugs excreted by the bile (e.g. doxorubicin and derivatives and vinca alkaloids). Validation studies comparing such recommendations with kinetics and/or dynamics of antineoplastic drugs in patients with decreased liver function have not been published. We conclude that there are currently not enough data for safe use of cyctostatics in patients with liver disease. Pharmaceutical companies should be urged to provide kinetic data (especially hepatic extraction data) for the classification of such drugs and to conduct kinetic studies for drugs with primarily hepatic metabolism in patients with impaired liver function to allow quantitative advice to be given for dose adaptation.

Dose adaptation of antineoplastic drugs in patients with liver disease.

There are over 150 documented methyltransferase enzymes, many with very different overall structures but with very similar properties within the local active site. Methyl conjugation is a good example of convergent evolution with over 95% of these enzymes using S-adenosyl-l-methionine (Ado-Met) as the methyl donor. Methyl transfer is an important pathway in the metabolism of both xenobiotic and endogenous compounds. Many drugs undergo methylation as do neurotransmitters, hormones, proteins, lipids, polysaccharides, and nucleic acids; methylation is fundamental to the control of gene transcription.

Nitrogen or oxygen atoms are the most common targets for protein methylation. N-Methylation in vivo is not readily reversible and the amino acid targets include lysine, histidine, arginine, glutamine, and asparagine. N-Methylation reactions play an important metabolic role in the termination of the action of histamine and in the formation of epinephrine from norepinephrine. O-Methylation targets include catechols, hydroxyindoles, and the carboxy groups of proteins and these reactions can be reversed. Thus, the reversible O-methylation of glutamates and aspartates produces methyl esters of a finite life span, which relate to protein function. The primary role of S-methylation is in the detoxification of xenobiotics. Thiopurine methyltransferase (TPMT) plays a key role in the metabolism of thiopurine anticancer and immunosuppressive drugs; there is no known endogenous substrate. The role played by the TPMT genetic polymorphism in the profound myelotoxicity induced by the thiopurine drugs azathioprine, mercaptopurine (MP), and thioguanine (TG) is a well-validated example of the clinical importance of pharmacogenetics; a textbook example of applied pharmacogenomic research.

This chapter concentrates on those human methyltransferases whose study has furthered our understanding of the fundamental role of methyl conjugation or whose analysis has illustrated basic concepts in the understanding of the methyl transfer reaction, that is, catechol O-methyltransferase (COMT, EC 2.1.1.6), histamine N-methyltransferase (HNMT, EC 2.1.1.8), thiol methyltransferase (TMT, EC 2.1.1.9), and TPMT (EC 2.1.1.67).

4.21 – Methyltransferases

The Liver in Systemic Illness

Fiedler, K., and K. Simons (1992) Protein sorting and detergent-insoluble complexes in MDCK cells. American Society for Cell Biology, Denver, Colorado, U.S.A. November 1992. Mol. Biol. of the Cell 3, supplement p308. Fiedler, K., Kellner, R., Dupree, P., Etzold, T., and K. Simons (1993) VIP36, a novel component of TGN-derived exocytic carrier vesicles and glycolipid-enriched rafts in MDCK cells. American Society for Cell Biology, New Orleans, U.S.A. December 1993. Mol. Biol. of the Cell 4, supplement p209.

https://edoc.unibas.ch/28421/1/Dissertation_Yves_J__Gschwind_print_20130428.pdf

Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der

Medication errors and adverse drug reactions are frequent in hospitalized patients.
The principle aim of my dissertation was to review the existing data about frequency and risk
factors of these findings and to propose measures for their reduction, focusing on the possibilities
of hospital pharmacists.
In more detail, the aims were:
– To review the literature published between 1990 and 2003 for studies reporting incidences
of medication errors and/or adverse drug effects in hospitals
– To investigate the prevalence of potential drug-drug interactions in ambulatory patients
treated with a statin
– To propose dosage guidelines for patients with liver disease being treated with antineoplastic
drugs. This study was initiated because questions about dose adaptation of antineoplastic
drugs are quite frequent in hospital pharmacies
In the first study, I analyzed the original publications about medication errors and/or adverse
drug reactions in hospitalized patients published between 1990 and 2003, with a focus
on frequency, risk factors and avoidance of problems associated with pharmacotherapy. I
performed a database search (Medline, Embase) for original articles using the terms „medication
error“, „adverse drug reaction“, “adverse event”, „hospital“ and supplemented the articles
retrieved by searching review articles for additional references. The analysis revealed
that medication errors occur with a frequency of approximately 5% of all drug applications,
with a high variability among the 29 studies retrieved. This variability is explained by the way
medication errors are detected (systematic screening of patients or charts vs. spontaneous
reports) and by the way drugs were administered (intravenous drugs have the highest error

frequency). Errors occur along the whole medication process, with application errors accounting
for more than 50% of them. Important risk factors are insufficient pharmacological
knowledge and work overload of the nursing staff, non-computerized transmission of prescriptions
and lack of clinical pharmacists on the wards. Adverse reactions affect approximately
6% of the patients per hospitalization and show a high variability between the 31 studies
retrieved. This variability can be explained by different assessment of the frequency of
adverse drug reactions and by the wards studied. Risk factors for adverse drug reactions include
female sex, age >65 years, polypharmacy and medication errors. These findings allowed
me to propose strategies for reducing medication errors, e.g. to improve the knowledge
about pharmacology of all persons involved in the medication process, computerization
of the entire medication process and the engagement of clinical pharmacists on the wards.
In the second study, we performed a cross-sectional analysis of the prevalence of potentially
serious drug-drug interactions of ambulatory dyslipidemic patients treated with a
statin. Data of patients with dyslipidemia treated with a statin were collected from 242 practitioners
from different parts of Switzerland. The medication was screened for potentially harmful
DDIs with statins or other drugs using an interactive electronic drug interaction program.
We included 2742 ambulatory statin-treated patients (mean age 65.1 ± 11.1 [SD] years;
61.6% males) with 3.2 ± 1.6 (mean±SD) diagnoses and 4.9 ± 2.4 drugs prescribed. Of those,
190 patients (6.9%) had a total of 198 potentially harmful drug-statin interactions. Interacting
drugs were fibrates or nicotinic acid (9.5% of patients with drug-statin interactions), CYP3A4-
inhibitors (70.5%), digoxin (22.6%) or cyclosporine (1.6%). The proportion of patients with a
potential drug-statin interaction was 12.1% for simvastatin, 10.0% for atorvastatin, 3.8% for
fluvastatin, and 0.3% for pravastatin. Additionally, the program identified 393 potentially critical
non-statin DDIs in 288 patients. Our study showed that CYP3A4 inhibitors are the most

frequent cause for potential interactions with statins. As the risk for developing rhabdomyolysis
is increased in patients having drug-statin interactions, clinicians should be aware of the
most frequently observed drug-statin interactions and how these interactions can be avoided.
In the third study, we classified the antineoplastic drugs marketed in Switzerland by the
end of 2003 according to their hepatic extraction in order to predict their kinetic behavior in
patients with liver disease and to give dose recommendations. Dose adaptation for liver disease
is important in patients treated with antineoplastic drugs due to the high prevalence of
impaired liver function in this population and the dose-dependent, frequently serious adverse
effects of these drugs. We therefore classified the antineoplastic drugs marketed in Switzerland
by the end of the year 2004 according to their bioavailability/hepatic extraction in order
to predict their kinetic behavior in patients with decreased liver function. This prediction was
compared with kinetic studies carried out with these drugs in patients with liver disease. Of
the 69 drugs identified, 52 had a predominant extrarenal (in most cases hepatic) metabolism
and/or excretion. For 48 drugs, hepatic extraction could be calculated and/or bioavailability
was available, allowing classification according to hepatic extraction. For 17 drugs, kinetic
studies have been reported in patients with impaired liver function, with the findings generally
resulting in quantitative recommendations for adaptation of the dosage. In particular, recommendations
are precise for 13 drugs excreted by the bile (e.g. doxorubicin and derivatives,
and vinca alkaloids). Validation studies comparing such recommendations with kinetics
and/or dynamics of antineoplastic drugs in patients with decreased liver function have not
been published, however. The study shows that there are currently not enough data for safe
use of antineoplastic drugs in patients with liver disease. We concluded that pharmaceutical
companies should be urged to provide kinetic data (especially hepatic extraction) used for
classification of such drugs and to conduct kinetic studies for drugs with primarily hepatic me

tabolism in patients with impaired liver function allowing to give quantitative advise for dose
adaptation.
The studies show that medication errors and adverse drug reactions are frequent in hospitalized
patients. Medication errors are an important risk factor for avoidable adverse drug
reactions. For two of them, drug-drug interactions and dose adaptation in patients with liver
disease, we performed studies focusing on the incidence and guidelines for their avoidance,
respectively. Hospital pharmacists have an important role both in the prevention and detection
of medication errors and adverse drug reactions.

/pdf/hospital-drug-safety-role-of-the-pharmacists-4pthazyram.pdf

Hospital drug safety - role of the pharmacists

Sir, The cytotoxic drug 6-mercaptopurine is a purine antagonist used in the remission maintenance regimes for standard risk childhood and adult acute lymphoblastic leukaemia. TheUK Medical Research Council (MRC) protocols for acute lymphoblastic leukaemia maintenance titrate the dose of both mercaptopurine and methotrexate according to biological response, ie, neutropenia and thrombocytopenia. Careful haematological monitoring is mandatory throughout maintenance therapy to avoid serious marrow toxicitiy, which may be prolonged. Mercaptopurine is reported to have hepatotoxic side effects such that dose reduction or withdrawal is advised in cases of hepatic impairment. We report a case of fatal hepatotoxicity without overt marrow suppression in the maintenance treatment of adult acute lymphoblastic leukemia. A 68-year-old man was referred to our unit in February 1994 for investigation of severe pancytopenia. Peripheral blood and bone marrow morphology together with immunophenotyping confirmed the diagnosis of pre-B acute lymphoblastic leukaemia. The patient underwent standard acute lymphoblastic leukaemia induction and early intensification regimes following entry to the MRC UK acute lymphoblastic leukaemia Xa trial. Maintenance therapy was delayed through prolonged cytopenia but was commenced in May 1994 and consisted of daily mercaptopurine 75 mg/ m2, weekly methotrexate 20 mg/M2 and monthly intravenous vincristine 1.5 mg/M2 with five-day courses of oral prednisolone 40 mg/ m2. Liver function tests were normal on starting maintenance therapy. Due to previous problems with cytopenia, 50% doses of mercaptopurine and methotrexate were introduced and then increased to a maximum of 75%. Therapy was well tolerated without cytopenia but with mild elevation in both serum alanine transaminase and aspartate transaminase with normal serum bilirubin levels. Shortly after the fifth monthly cycle of vincristine, prednisolone, mercaptopurine and methotrexate, all treatment was stopped due to a marked elevation in serum bilirubin to 155 limol/l (normal range 1 -24 limol/l), aspartate transaminase 182 IU/1 (normal range 5-40 IU/1), alanine transaminase 149 IU/1 (normal range 7-56 IU/1) and alkaline phosphatase 143 IU/1 (normal range 36-125 IU/1). Apart from oral frusemide there was no other concomitant therapy taken. Ultrasound examination excluded biliary obstruction. Hepatitis serology and microbiological cultures were negative. Liver function continued to deteriorate with progressive jaundice, bilirubin rising to 600 ,lmol/l, aspartate transaminase to 132 IU/1, and alkaline phosphatase to 152 IU/1. In spite of intensive supportive therapy his condition deteriorated, developing hepatic encephalopathy with renal failure resulting finally in death. Post-mortem examination showed no evidence of biliary obstruction. Autopsy histology revealed marked intracellular and intracannalicular cholestasis, focal bile infarcts and mild 6-Mercaptopurine

https://pmj.bmj.com/content/postgradmedj/71/840/639.1.full.pdf

Fatal hepatotoxicity associated with 6-mercaptopurine therapy.

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Fatal hepatotoxicity associated with 6-mercaptopurine therapy.