**Core Concept**
Methotrexate, a folate antagonist, is used in cancer chemotherapy and autoimmune disease treatment. Its effectiveness and toxicity are influenced by its metabolism and excretion, particularly in the kidneys. Maintaining a high urinary pH is crucial during methotrexate treatment to enhance its excretion.

**Why the Correct Answer is Right**
Methotrexate is primarily excreted by the kidneys, and its clearance is significantly increased at alkaline urinary pH. This is because methotrexate is a weak acid, and its ionization increases in alkaline conditions, leading to its increased solubility and excretion in the urine. The kidneys' ability to secrete organic anions, such as methotrexate, is enhanced at alkaline pH, further increasing its clearance.

**Why Each Wrong Option is Incorrect**
**Option A:** This option is incorrect because maintaining high urinary pH does not enhance methotrexate's cellular uptake or inhibit its cellular efflux.

**Option B:** This option is incorrect because methotrexate's efficacy is not directly related to its plasma protein binding, which is not affected by urinary pH.

**Option C:** This option is incorrect because methotrexate's metabolism to its active metabolite, 7-hydroxymethotrexate, is not influenced by urinary pH.

**Clinical Pearl / High-Yield Fact**
Methotrexate's toxicity is closely related to its plasma and tissue levels, and maintaining high urinary pH can help reduce its toxicity by enhancing its excretion.

**Correct Answer:** C.