Drug Class

Generic Name

(Trade Name)

Absorption

Distribution

Elimination Alkylating Agents

melphalon

(Alkeran)

oral - variably and incompletely absorbed from the GI tract, decreased in presence of food

moderately high protein binding, Vz 0.5 l/kg

deactivated in plasma by hydrolysis

cyclophosphamide

(Cytoxan)

oral - high bioavailability; intravenous

crosses blood-brain barrier (limited)

hepatic biotransformation (includes activation); 5 - 25% eliminated unchanged (renal); parent and metabolites eliminated in urine are toxic to bladder

ifosfamide

(Ifex)

intravenous infusion only

active metabolites cross blood-brain barrier (limited)

hepatic biotransformation (includes activation); 10 - 60% eliminated unchanged (increases with increasing dose - renal); parent and metabolites eliminated in urine are toxic to bladder

busolfan

(Myleran)

oral - completely absorbed from GI tract

rapid hepatic biotransformation

procarbazine

(Matulane)

oral - Rapidly and completely absorbed from the gastrointestinal tract.

Crosses blood-brain barrier.

Hepatic biotransformation, very short elimination half-life. 70% renal elimination as metabolites.

dacarbazine

(Otic-Dome)

Intravenous only

limited access to CNS; low protein binding

Extensive hepatic biotransformation; 50% renal elimination (1/2 unchanged).

Antibiotics

daunorubicin

(Cerubidine)

intravenous only

body water, excluded by blood-brain barrier

hepatic metabolism produces both active and inactive metabolites.

daunorubicin or doxorubicin liposomes

(Daunoxome or Doxil)

intravenous infusion only

limited to vascular fluid, animal studies indicate delivery to CNS; tissues selectively "acquire" liposomes.

greatly reduced hepatic metabolism compared to un-encapsulated drug

doxorubicin

(Adriamycin)

intravenous only

high protein binding; extensive uptake into many tissues, does not cross blood-brain barrier

hepatic metabolism produces both active and inactive metabolites; tissue metabolism results in production of free radicals.

idarubicin

(Idamycin)

intravenous infusion only

extensive tissue binding of both native drug and metabolite; very high plasma protein binding

hepatic and extrahepatic metabolism to equipotent metabolite; elimination primarily biliary as active metabolite.

plicamycin

(Mithracin)

intravenous infusion only

crosses blood-brain barrier, concentrated in Kupffer cells, renal tubular cells and bone surfaces

elimination is renal

mitomycin (Mutamycin)

intravenous only

does not cross blood brain barrier

hepatic biotransformation, 10% eliminated in urine unchanged (% increases as dose increases)

pentostatin

(Nipent)

intravenous only

crosses blood-brain barrier (CSF concentrations ~10% of plasma concentrations within 24 hours). Low plasma protein binding

hepatic biotransformation, 30% - 70% eliminated in urine as unchanged drug

mitoxantrone

(Novantrone)

intravenous infusion only

rapid extensive distribution to tissues; high protein binding

hepatic; long half-life (due to tissue binding & slow metabolism); small fraction eliminated unchanged.

dactinomycin

(Cosmegen)

intravenous only

does not cross blood brain barrier

Minimal biotransformation; Elimination primarily biliary/fecal 50% unchanged (24 hours), another 10% unchanged in urine (24 hour); remainder of the drug is recovered within 1 week.

Antimetabolites

fluorouracil

(Adrucil)

intravenous only

good tissue penetration, crosses blood brain barrier

hepatic metabolism produces 2 active metabolites and catabolism; respiratory elimination as carbon dioxide; 7 - 20% unchanged in urine

capecitabine

(Xeloda)

oral (pro drug)

as for fluorouracil

hepatic activation by conversion to 5 fluorouracil; elimination pattern as for 5 flurouracil

fludarabine

(Fludara)

intravenous only

distributed to whole body water

RAPIDLY dephosphylated in serum to 2-fluoro-Ara-A, then phosphorylated intracellularly to active compound. Elimination is renal, approximately 20% unchanged 2-fluoro-Ara-A

mercaptopurine

(Purinethol)

oral - variably and incompletely absorbed from the GI tract (up to 50%)

Crosses blood-brain barrier but poorly; low protein binding

Hepatic metabolism for both activation and catabolism; degraded by xanthine oxidase; 7 - 40% eliminated unchanged.

gemcitabine

(Gemzar)

intravenous infusion only

distribution of active metabolite is limited by saturable process. Giving gemcitabine at an excess rate WASTES drug (eliminated intact before conversion).

Intracellular metabolism (saturable) to active metabolites. Hepatic deamination to inactive uracil metabolite.

Hormonal Oncologics

topotecan

(Hycamtin)

intravenous infusion only

good tissue penetration, volumes approximately 2x body water, crosses blood brain barrier

reversible pH-dependent hydrolysis to inactive moeity (low pH favors active compound), hepatic metabolism insignificant; 30% eliminated unchanged in urine

leuprolide

(Lupron)

IM injection - 90% bioavailability; 1 month, 3 month and 4 month release formulations

distributed to extracellular fluid volume; moderate (50%) protein binding.

Metabolized to several inactive peptides. Less than 5% recovered as parent or pentapeptide metabolite.

tamoxifen

(Nolvadex)

oral administration, bioavailability?

Hepatic biotransformation with enterohepatic circulation. Prolonged elimination; Elimination primarily biliary/fecal, mostly as metabolites

Mitosis inhibitors

etopside

(VP16)

oral - variable dose-dependent oral bioavailability (F decreases as dose increases); intravenous

Low and variable into CSF, concentration differentials between normal and cancerous tissues. Very high protein binding (97%). Protein displacement interactions and hypoalbuminemia are concerns.

Hepatic biotransformation; up to 50 - 60% renal elimination (2/3 as unchanged drug); remainder fecal.

Others

hydroxyurea

(Hydrea)

Well absorbed following oral administration.

Crosses the blood-brain barrier (very small molecular weight).

Hepatic metabolism (inactivation), 80% renal elimination within 12 hours (50% unchanged); balance eliminated from lungs as CO2

paclitaxel

(Taxol)

intravenous only

extensive extravascular distribution and/or tissue binding. Very high plasma protein binding.

Hepatic p450 metabolism. Elimination primarily biliary / fecal. Variable renal elimination of unchanged drug.

docetaxel

(Taxotere)

intravenous only

widely distributed in tissues; slightly larger than body water; poor CNS penetration.

Hepatic p450 metabolism. Elimination primarily biliary / fecal.

cisplatin

(Platinol)

intravenous only

does not penetrate CNS

rapid non-enzymatic conversion to inactive metabolites. Elimination usually expressed as recovered platinum (only 50% after 5 days), platinum detected in tissues for months.

aspariginase

(Elspar)

intravenous

intramuscular

slow sequestration by reticuloendothelial system; poor CNS penetration

unknown pathway, only trace amounts appear in the urine following IV administration.

Anti-toxicity

amifostine

(Ethyol)

intravenous infusion only

wide rapid distribution

metabolised by alkaline phosphatase to active free thiol metabolite (binds cisplatin metabolites and alkylating agents and scavanges free radicals. Reaction favored in normal tissues (higher AP)

dexrazoxane

(Zinecard)

intravenous only

distributed to whole body water, low protein binding

several hepatic metabolites, intracellular metabolite may be responsible for action though this is speculative at this time

mesna

(Mesnex)

intravenous only

volume of distribution approximates body water.

rapid hepatic biotransformation to mesna disulfide; mesna disulfide is reduced to mesna by renal tubular epithelium, mesna binds and detoxifies metabolites of oxazophosphorines.

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