Drug Interactions

This page is intended to point out well-known pharmacokinetic and pharmacodynamic interactions between drugs commonly used by glioma patients in multi-agent drug and supplement “cocktails”.

PHARMACOKINETIC INTERACTIONS

According to the Free Dictionary (online), pharmacokinetics refers to “the action of drugs in the body over a period of time, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion”. It refers to the amount or concentration of a drug in plasma or tissues, and the rate of its absorption and clearance from the body. The following pharmacokinetic interactions between drugs commonly used in drug cocktails by glioma patients have been reported in the literature.

CIMETIDINE AND SILDENAFIL

Cimetidine is a mild inhibitor of CYP3A4, the main hepatic enzyme responsible for sildenafil metabolism.

In one study (1), when a group of volunteers took 800 mg cimetidine two hours before 50 mg of sildenafil, the maximum plasma concentration of sildenafil was increased by 54% compared to the group taking sildenafil plus placebo. Co-administration with cimetidine did not affect the tolerability of 50 mg sildenafil. “No clinically significant changes in blood pressure and pulse rate or abnormalities in ECG were reported”. For daily usage, lower dose of sildenafil is recommended (for example 20 mg Revatio, or cheaper generic equivalent).

CIMETIDINE AND CHLOROQUINE

Cimetidine is a mild inhibitor of CYP3A4, one of the hepatic enzymes responsible for chloroquine metabolism.

In a study from 1987 (2) 400 mg cimetidine was taken by volunteers at 10pm for four nights followed by 300 mg chloroquine (as chloroquine sulfate) at 8am on the fifth day. The clearance rate of chloroquine was reduced by 53%, and the elimination half-life was increased by 49% in the group also taking cimetidine compared with the control group. According to figure 1 of the study, the maximum serum concentration of chloroquine was increased by roughly 30% in the group also taking cimetidine.

Though this increase in plasma concentrations of chloroquine when taken after cimetidine does not necessarily lead to adverse events when taken over short periods, patients should be aware of the possible adverse side-effects of chloroquine, especially with longer term usage. 250 mg chloroquine phosphate (the equivalent of 150 mg chloroquine base) per day is the dose commonly used by glioma patients to potentiate radio- and chemotherapy. This is also a dose of chloroquine used on a daily basis to treat rheumatoid arthritis.

CIMETIDINE AND METFORMIN

Cimetidine is a competitive inhibitor of OCT2 (organic cation transporter 2). This transporter is responsible for the transport of metformin into the proximal tubular cells in the kidney, and is thus involved in the renal clearance of metformin.

In a study published in 1987 (4), seven volunteers took 250 mg of metformin hydrochloride (half a Glucophage tablet) each day for 10 days. On days 6-10, the volunteers also took 400 mg cimetidine twice daily. Maximum plasma concentration of metformin increased by 73% when patients were co-administered cimetidine. Renal clearance of metformin was reduced by 27% on average.

A metformin dosage of 500 mg twice daily (1000 mg per day) is commonly taken by glioma patients as part of a drug/supplement cocktail, and is fairly well tolerated. Total daily doses of up to 2000 mg per day or higher are sometimes prescribed to diabetic patients. Tolerance to metformin increases with long-term use. The most common side-effects of metformin are diarrhea, nausea and upset stomach. Metformin dosing should be adjusted according to individual tolerance, whether the person is also taking cimetidine or not. Take metformin with meals to reduce chance of gastrointestinal symptoms.

CIMETIDINE SUMMARY

“Although cimetidine interacts with a large number of drugs, reports of incidents of drug toxicity are uncommon. This may be due to the fact that physicians are well aware of those drugs with a narrow therapeutic index which interact clinically with cimetidine and have taken appropriate action, or the fact that the majority of drugs have a wide therapeutic index, so that a 50% increase in plasma concentration would not be deleterious to the patient.”

Quote from Somogyi A, and Muirhead M. “Pharmacokinetic interactions of cimetidine 1987.” Clinical Pharmacokinetics, May 1987.
Abstract

PHARMACODYNAMIC INTERACTIONS

In contrast with pharmacokinetics (see description above), pharmacodynamics is “the study of the mechanisms of action of drugs and other biochemical and physiological effects”.

DISULFIRAM AND SERTRALINE ORAL CONCENTRATE SOLUTION

Sertraline (Zoloft) is available in two forms: tablets or oral concentrate solution. The oral concentrate contains 12% alcohol, and should therefore be avoided by patients also taking disulfiram.

DISULFIRAM AND DICHLOROACETATE (DCA)

Both of these drugs may lead to peripheral neuropathy, characterized by tingling, burning, needles and pins, pain or numbness, especially in hands and feet. Risk of neuropathy may be increased by combining more than one drug that can have this outcome.

A controlled randomized clinical trial (6) for patients with disorders characterized by high levels of lactate found that 12.5 mg/kg twice daily of DCA led to peripheral neuropathy in 19 of 22 patients, with 79% of these cases becoming apparent within 3 months of treatment. The most common symptom was “distal limb paresthesias.”

Paresthesias (including “pins and needles”) and numbness in hands and feet is also a potential side-effect of disulfiram at doses of 500 mg per day, and even as low as 250 mg per day. One study (7) reported a median interval of 5.5 months (time from start of treatment to symptoms) for those experiencing neuropathy on disulfiram.

Chloroquine treatment has also been associated with peripheral neuropathy in rare cases (8), though unlike disulfiram and DCA, the symptom of chloroquine neuropathy tends to be weakness of the quadriceps muscles (front of the thigh).

MINOCYCLINE AND ACCUTANE (ISOTRETINOIN)

Tetracycline antibiotics such as minocycline and retinoids such as isotretinoin (Accutane) have both been linked with the potential side effect of pseudotumor cerebri, also called idiopathic intracranial hypertension. This risk is likely increased when both types of drug are taken together (5), and this combination is considered to be contraindicated.

REFERENCES

1. The effects of cimetidine and antacid on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers. Wilner et al. 2002.
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2. Chloroquine elimination in humans: effect of low-dose cimetidine. Ette et al. 1987.
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3. Chloroquine Retinopathy in Patients with Rheumatoid Arthritis. Elman et al. 1976.
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4. Reduction of metformin renal tubular secretion by cimetidine in man. Somogyi et al. 1987.
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5. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Lee, 1995.
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6. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Kaufmann et al. 2006.
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7. Disulfiram neuropathy. Watson et al. 1980.
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8. Peripheral Neuropathy Following Chloroquine Therapy. Loftus, 1963.
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