Pharmacokinetic Considerations in Cancer Chemotherapy

PHARMACOKINETIC CONSIDERATIONS IN CANCER CHEMOTHERAPY

Pharmacokinetic Sanctuaries

The existence of the blood-brain barrier is an important consideration in the chemotherapy of neoplastic dis-eases of the brain or meninges. Poor drug penetration into the CNS has been a major cause of treatment fail-ure in acute lymphocytic leukemia in children. Treatment programs for this disease now routinely em-ploy craniospinal irradiation and intrathecally adminis-tered methotrexate as prophylactic measures for the prevention of relapses. The testes also are organs in which inadequate antitumor drug distribution can be a cause of relapse of an otherwise responsive tumor.

The multidrug transporter P-glycoprotein is ex-pressed in the endothelial lining of the brain and testis but not in other organs and is thought to be a major component of the blood-brain and blood-testis drug barriers.

Schedules of Administration

Although the effects of various schedules are not al-ways predictable, drugs that are rapidly metabolized, excreted, or both, especially if they are phase specific and thus act on only one portion of the cell cycle (e.g., cytarabine), appear to be more effective when adminis-tered by continuous infusion or frequent dose fraction-ation than by high-dose intermittent therapy. On the other hand, intermittent high-dose treatment of Burkitt’s lymphoma with cyclophosphamide is more ef-fective than fractionated treatment, since cyclophos-phamide acts on all phases of the cell cycle and almost all of the tumor cells in that disease are actively prolif-erating.

The classic example of schedule dependency is cy-tarabine, a drug that specifically inhibits DNA synthesis and is cytotoxic only to cells in S-phase. Continuous in-fusion or frequent administration of cytarabine hy-drochloride is superior to intermittent injection of the drug. Bleomycin is another drug for which continuous infusion may increase therapeutic efficacy.

Administration of some anticancer drugs by contin-uous infusion has been shown to improve their thera-peutic index through selective reduction of toxicity with retained or enhanced antitumor efficacy.

Routes of Administration

In addition to the usual intravenous or oral routes, some anticancer agents have been administered by regional intraarterial perfusion to increase drug delivery to the tumor itself and at the same time diminish systemic tox-icity. Thus, patients with metastatic carcinomas of the liver and little or no disease elsewhere (a common oc-currence in colorectal cancer) can be treated with a con-tinuous infusion of fluorouracil or floxuridine through a catheter implanted in the hepatic artery.

Intracavitary administration of various agents has been used for patients with malignant pleural or peri-toneal effusions. Intraperitoneal instillations of cisplatin, etoposide, bleomycin, 5-fluorouracil, and interferon are well tolerated and are being evaluated in patients with ovarian carcinomas, in whom the tumor is frequently re-stricted to the peritoneal cavity.

Other routes of administration can be employed in certain situations. Methotrexate and cytarabine are given intrathecally or intraventricularly to prevent re-lapses in the meninges in acute lymphocytic leukemia and to treat carcinomatous meningitis. Thiotepa and bleomycin have been administered by intravesical in-stillation to treat early bladder cancers. Fluorouracil can be applied topically for certain skin cancers.

Drug Interactions

Antineoplastic drugs may participate in several types of drug interactions. Methotrexate, for example, is highly bound to serum albumin and can be displaced by sali-cylates, sulfonamides, phenothiazines, phenytoin, and other organic acids. The induction of hepatic drug-metabolizing enzymes by phenobarbital may alter the metabolism of cyclophosphamide to both active and in-active metabolites. Mercaptopurine metabolism is blocked by allopurinol, an occurrence that may result in lethal toxicity if the dosage of mercaptopurine is not re-duced to one-fourth of the usual dosage. Methotrexate is secreted actively by the renal tubules, and its renal clearance may be delayed by salicylates.

Procarbazine exhibits an interesting interaction with ethanol, resulting in headaches, diaphoresis, and facial erythema; patients taking this drug should be fore-warned to abstain from alcohol. Procarbazine is also a monoamine oxidase (MAO) inhibitor and may potenti-ate the effects of drugs that are substrates for this en-zyme.

The biliary and renal excretion of some drugs (e.g., anthracyclines, vinca alkaloids, dactinomycin, etopo-side) by the P-glycoprotein multidrug transporter can be inhibited by other drugs that are also transported by P-glycoprotein.